TW202136268A - Pyrrolo[1,2-b]pyridazine derivatives - Google Patents

Abstract

A compound of Formula (I):

Description

Pyrrolo[1,2-B]ta 𠯤 derivative

The present invention relates to novel compounds that are inhibitors of the kinase IRAK4. The present invention also relates to methods for preparing these compounds and pharmaceutical compositions containing these compounds.

Interleukin-1 receptor-related kinase-4 (IRAK4) is a serine-threonine kinase that acts as one of the interleukin-1/todor-like receptor (IL-1/TLR) signaling cascades Mediator. More specifically, IRAK4 is involved in the activation of the attachment protein myeloid differentiation factor primary response gene 88 (MyD88) signaling cascade, and is hypothesized to play a role in inflammation and fibrotic conditions, such as rheumatoid joints. Inflammation (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjogren's syndrome (Sjogren's) syndrome), viral myocarditis, acute and chronic tissue damage, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis and nephropathy (including chronic kidney disease and diabetic nephropathy). In addition, IRAK4 plays a role in certain cancers and is hypothesized to play a role in inflammation associated with gastrointestinal infections, including C. difficile . Signaling via IL-1R/TLR causes the activation of MyD88, which replenishes IRAK4 and IRAK1 to form a signaling complex. This complex then interacts with a series of kinases, attachment proteins, and ligases, and finally causes the nuclear factor kappa light chain enhancer (NF-κB), activator protein-1 (AP1), and cyclic AMP- which activate B cells. The activation of reactive element-binding protein (CREB) and interferon regulatory factor (IRF) (including IRF5 and IRF7) induces the production of pro-inflammatory cytokines and type I interferons.

Therefore, IRAK4 inhibitors can be suitable for the treatment of inflammatory and fibrotic diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory diseases , Systemic lupus erythematosus (SLE), Hugherian syndrome, inflammation associated with gastrointestinal infections (including Clostridium difficile), viral myocarditis, acute and chronic tissue damage, non-alcoholic steatohepatitis (NASH) , Alcoholic hepatitis and nephropathy (including chronic kidney disease and diabetic nephropathy). (Joosten, LAB and others , TOLL-LIKE RECEPTORS AND CHRONIC INFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev. Rheumatol., 346 | June 12, 2016; 344-357, published online May 12, 2016) ( Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1RECEPTOR-ASSOCIATED KINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5 ⁺ CD11b ⁺ MONOCYTE MIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circuit, 128 | September 14, 2013; I1542-1554), and Type I interferonopathy (Type I interferonopathy), such as Aicardi-Goutières syndrome (Aicardi-Goutières syndrome), familial frostbite-like lupus and retinal vascular disease associated with cerebral leukodystrophy ( Lee-Kirsch et al. , TYPE I INTERFERONOPATHIES-AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349-357), ( Leaf, IA et al., PERICYTE MYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTIC RESPONSES TO TISSUE INJURY, The Journal Investigation, 127 | JANUARY 2017 1; 321-334), ( Seki, E. et al., TLR4 ENHANCES TGF- β SIGNALING AND HEPATIC FIBROSIS, Nature Medicine, 13 | NOVEMBER 2007 11; 1324-1332), ( Garcia-Martinez, I. et al., HEPATOCYTE MITOCHONDRIAL DNA DRIVES NONALCHOLIC STEATOHEP ATITIS BY ACTIVATION OF TLR9, The Journal of Clinical Investigation, 126 | MARCH 2016 3; 859-864).

In addition, certain cancers, including lymphoma, may contain one or more mutations in the MYD88 attachment protein, resulting in a constitutively active signal cascade that promotes tumor cell survival. (Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp. Med. 2015, Volume 212, Issue 13, 2189-2201)

Therefore, IRAK4 inhibitors can be suitable for the treatment of cancers including lymphoma.

There are currently no approved IRAK4 inhibitors. Therefore, it would be useful to provide an IRAK4 inhibitory compound that has the characteristics of being suitable for administration as a medicament to mammals, in particular, administration to humans. The considerations for selecting pharmaceutical compounds are multi-factorial. Compound characteristics are often analyzed, including target efficiency, pharmacokinetics, pKa, solubility, stability (such as metabolic stability) and off-target tendency (including potential cardiotoxicity), as well as potential drug-drug interactions.

The inhibition of cardiac ion channels coded by the human ether-à-gogo-related gene (hERG) can cause arrhythmia, which is a major problem in drug discovery and development. Automated electrophysiological patch clamp allows evaluation of hERG channel effects in early drug development to assist medicinal chemistry procedures and has become a routine for pharmaceutical companies. Early identification of hERG liability in drug discovery programs by automated patch clamp , Front Pharmaco. (September 2, 2014); 5: 203.

WO2016210034, WO2016210036, WO2015150995, WO2016127024 and WO2016210037 enumerate compounds that are said to be suitable as IRAK4 inhibitors.

Provided herein are compounds and pharmaceutical compositions suitable as inhibitors of IRAK4. Some of the compounds of the present invention can be used in pharmaceutical compositions with at least one pharmaceutically acceptable excipient for the treatment of individuals in need. It has also been found that the compounds of the present invention inhibit the production of pro-inflammatory cytokines TNFα, IL-6, IL-1β, IL-8, IL-12, IL-23 and type I interferons IFNα and IFNβ, all of which are inflammatory And the mediator of the immune response. The present invention also provides compositions including these compounds, including pharmaceutical compositions, kits, and methods of using and preparing these compounds.

或其醫藥學上可接受之鹽或結構異構體，其中： R¹ 選自H、氘或C_1-4 烷基，且該C_1-4 烷基視情況經一或多種鹵基取代； R² 選自H、氘或C_1-4 烷基，且該烷基視情況經一或多種鹵基取代；或 R¹ 及R² 連同其所附接之碳原子一起形成C3-C6環烷基；且 R³ 為C₀-₄ 烷基-CN。In one embodiment of the present invention, a compound of formula (I) is provided:

Or a pharmaceutically acceptable salt or structural isomer thereof, wherein: R ^{1 is} selected from H, deuterium or C _1-4 alkyl, and the C _1-4 alkyl is optionally substituted with one or more halo groups; R ^{2 is} selected from H, deuterium or C _1-4 alkyl, and the alkyl is optionally substituted with one or more halo groups; or R ¹ and R ² together with the carbon atoms to which they are attached form a C3-C6 cycloalkane And R ³ is C _{0 -4} alkyl-CN.

In one embodiment, R ² is H.

In one embodiment, R ¹ is methyl.

In one embodiment, R ³ is -CN.

或其醫藥學上可接受之鹽或結構異構體，其中： R¹ 選自H、氘或C_1-4 烷基，且該C_1-4 烷基具有一或多個視情況經氘置換之氫原子； R² 選自H、氘或C_1-4 烷基，且該C_1-4 烷基具有一或多個視情況經氘置換之氫原子；且 R³ 為C₀-₄ 烷基-CN。In another embodiment, a compound of formula II is provided:

Or a pharmaceutically acceptable salt or structural isomer thereof, wherein: R ^{1 is} selected from H, deuterium or C _1-4 alkyl, and the C _1-4 alkyl has one or more optionally substituted with deuterium the hydrogen atom; R ² is selected from H, deuterium or C _1-4 alkyl and the C _1-4 alkyl group optionally having one or more hydrogen atoms are replaced with the deuterium; and R ³ is C ₀ - ₄ alkyl基-CN.

In an embodiment of formula (II), R ² is H.

In another embodiment, R ² is deuterium.

In an embodiment of formula (II), R ¹ is a methyl group.

In one embodiment of formula (II), R ¹ is a methyl group, wherein one or more of the hydrogen atoms attached to the methyl group are replaced with deuterium.

In one embodiment, R ³ is -CN.

， 或其醫藥學上可接受之鹽，或氘化類似物，其中： R¹ 選自H、氘或甲基，且該甲基具有一或多個視情況經氘置換之氫原子。In another embodiment, a compound of formula (III) is provided:

, Or a pharmaceutically acceptable salt thereof, or a deuterated analog, wherein: R ^{1 is} selected from H, deuterium, or methyl, and the methyl group has one or more hydrogen atoms replaced by deuterium as appropriate.

； 或其醫藥學上可接受之鹽。In one embodiment, a compound having the following structure is provided:

; Or its pharmaceutically acceptable salt.

In one embodiment, a pharmaceutical composition is provided, which comprises the compound herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier and optionally a diluent.

Another embodiment of the present invention provides a method of treating inflammation-related diseases or disorders in a patient in need, the method comprising administering a compound of the present invention or a pharmaceutical composition thereof to the patient.

Definitions The following description sets forth exemplary methods, parameters, and the like. However, it should be appreciated that this description is not intended to be a limitation on the scope of the present invention, and it is true that this description is provided as a description of exemplary embodiments.

A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of substituents. For example, -C(O)NH ₂ is connected via a carbon atom. The dashes at the front or end of the chemical group are for convenience; the chemical group can be depicted with or without one or more dashes without losing its ordinary meaning. The wavy line drawn through the line in the structure indicates the connection point of the group. Unless required chemically or structurally, the order in which chemical groups are written or named does not indicate or imply directionality.

The prefix "C _uv "indicates that the following groups have u to v carbon atoms. For example, "C _1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. C ₀ indicates that no carbon is present, or in other words, a bond to the next substituent.

Reference herein to "about" a certain value or parameter includes (and describes) an embodiment for the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about X" includes the description of "X". In addition, unless the context clearly dictates otherwise, the singular forms "一(a)" and "the (the)" include plural references. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the test" includes reference to one or more tests and equivalents known to those familiar with the art.

"Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e. C _1-20 alkyl), 1 to 8 carbon atoms (i.e. C _1-8 alkyl), 1 to 6 carbon atoms ( That is, C _1-6 alkyl) or 1 to 4 carbon atoms (ie, C _1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, second butyl, isobutyl, tertiary butyl, pentyl, 2-pentyl, isopentyl, neopentyl Base, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When the residue of an alkyl group with a specific number of carbon atoms is identified by a chemical name or by a molecular formula, all positional isomers with that number of carbon atoms can be covered; thus, for example, "butyl" includes n-butyl Group (i.e. -(CH ₂ ) ₃ CH ₃ ), second butyl group (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl group (i.e. -CH ₂ CH(CH ₃ ) ₂ ) and Tertiary butyl (ie -C(CH ₃ ) ₃ ); and "propyl" includes n-propyl (ie -(CH ₂ ) ₂ CH ₃ ) and isopropyl (ie -CH(CH ₃ ) ₂ ).

"Cyano" refers to the group -CN.

"Halo" refers to -F, -Cl, -Br, -I.

Some common alternative chemical names can be used. For example, divalent groups such as divalent "alkyl" and divalent "aryl" can also be referred to as "alkylene or alkylenyl" and "arylene or arylenyl", respectively. In addition, unless expressly indicated otherwise, a combination of groups is referred to herein as a moiety, such as an aralkyl group, and the last-mentioned group contains an atom that connects the moiety to the rest of the molecule.

The term "depending on the situation" or "depending on the situation" means that the event or situation described later may or may not occur, and the description includes the situation in which the event or situation occurs and the situation in which the event or situation does not occur. In addition, the term "optionally substituted" means that any one or more of the hydrogen atoms on the designated atom or group may be replaced by parts other than hydrogen or may not be replaced. "Substituted as appropriate" can be from zero to the maximum number of possible substitutes, and each occurrence is independent. When the term "substituted" is used, it is required to perform that substitution at the replaceable hydrogen atom of the designated substituent. Depending on the circumstances, the substitution may be the same as or different from the (required) substitution.

When the part is "optionally substituted" and mentions such as any "alkyl", "alkenyl", "alkynyl", "haloalkyl", "cycloalkyl", "aryl" or "heteroaryl" When the general term is used, the general term can refer to any term that precedes the exact description, such as (C _1-3 alkyl), (C _{4 -6} alkyl), -O (C _1-4 alkyl), (C _3-10 cycloalkyl), O-(C _3-10 cycloalkyl) and similar groups. For example, "any aryl" includes "aryl" such as phenyl or naphthyl and the like. In addition, the term "any heterocyclic group" includes heterocyclic groups such as oxetanyl, tetrahydropiperanyl, morpholinyl, piperidinyl, and the like. In the same way, the term "any heteroaryl" includes the term heteroaryl, such as pyridine, titan, thiazole, thiadiazole, quinoline, and similar groups.

Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, the amide-containing compound may exist in equilibrium with the imine tautomer. Regardless of which tautomers are displayed and regardless of the equilibrium properties between the tautomers, those skilled in the art generally understand that compounds include both amide and imine tautomers. Therefore, the amide-containing compound should be understood to include its imine tautomers. Likewise, an imine acid-containing compound should be understood to include its amide tautomers.

Any formula or structure given herein is also intended to represent the unlabeled form and the isotope-labeled form of the compound. Isotopically labeled compounds have the structure described by the formula given herein, with the exception that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as (but not limited to) ² H (deuterium, D), ³ H (tritium), ¹¹ C , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ¹⁵ O, ¹⁸ O, 3 ¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. The compounds of the present invention labeled with various isotopes are, for example, those compounds in which ^{radioisotopes such as 3} H, ¹³ C, and ¹⁴ C are incorporated. Such isotopically-labeled compounds can be applied to metabolic studies, reaction kinetics studies, detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drugs or subject Qualitative tissue distribution analysis) or for radiotherapy of patients.

The present invention also includes "deuterated analogs" of compounds of formula I, in which 1 to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased metabolic resistance and are therefore suitable for increasing the half-life of any compound of formula I when administered to mammals (especially humans). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

The deuterium-labeled or substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, which are related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes (such as deuterium) can result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, decreased dosage requirements, and/or improved therapeutic index. Compounds labeled with ¹⁸ F are suitable for PET or SPECT research. The isotopically-labeled compounds and prodrugs of the present invention can generally be performed by following the procedures or examples described below and the procedures disclosed in the preparation, by replacing the non-isotopically-labeled reagents with readily available isotopically-labeled reagents To prepare. It should be understood that in this context, deuterium is considered a substituent in the compound of formula I.

The concentration of such heavier isotopes (deuterium to be exact) can be defined by the isotope enrichment factor. In the compounds of the present invention, any atom that is not specifically designated as a specific isotope is intended to mean any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it should be understood that the position has hydrogen in its natural abundance isotopic composition. Therefore, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.

In many cases, the compounds of the present invention can form acid and/or alkali salts by virtue of the presence of amine groups and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other substances suitable for preparing pharmaceutical compositions suitable for veterinary or human medicine.

The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the conventional procedure for preparing acid addition salts from base compounds can be followed by dissolving the free base in a suitable organic solvent and treating the solution with an acid to produce addition salts, especially Pharmaceutically acceptable addition salt. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, the salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, and tertiary amines, such as alkylamines (ie, NH ₂ (alkyl)), dialkylamines (also That is, HN (alkyl) ₂ ), trialkylamine (that is, N (alkyl) ₃ ), substituted alkylamine (that is, NH ₂ (substituted alkyl)), two (by Substituted alkyl) amines (ie, HN (substituted alkyl) ₂ ), tris (substituted alkyl) amines (ie, N (substituted alkyl) ₃ ), alkenyl amines (also That is, NH ₂ (alkenyl)), dienyl amine (that is, HN (alkenyl) ₂ ), trienyl amine (that is, N (alkenyl) ₃ ), substituted alkenyl amine (also That is, NH ₂ (substituted alkenyl)), two (substituted alkenyl) amine (that is, HN (substituted alkenyl) ₂ ), tris (substituted alkenyl) amine (that is, N (substituted alkenyl) ₃ , monocyclic alkylamine, dicycloalkylamine or tricyclic alkylamine (ie, NH ₂ (cycloalkyl), HN (cycloalkyl) ₂ , N(cyclic Alkyl) ₃ ), monoarylamine, diarylamine or triarylamine (ie, NH ₂ (aryl), HN(aryl) ₂ , N(aryl) ₃ ) or mixed amines, etc. only. For example, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, Piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

The term "substituted" means that any one or more hydrogen atoms on the designated atom or group is replaced by one or more substituents other than hydrogen, and the restriction is that the normal valence of the designated atom is not exceeded. One or more substituents include (but are not limited to) alkyl, alkenyl, alkynyl, alkoxy, acyl, amine, amide, formamidino, aryl, azido, carbamoyl , Carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, pendant oxy, nitro Group, alkylsulfinyl, sulfonic acid, alkylsulfinyl, thiocyanate, thiol, thioketone, or a combination thereof. By using infinitely additional substituents (for example, a substituted aryl group with a substituted alkyl group, the substituted alkyl group itself is substituted by a substituted aryl group, the substituted aryl group is further substituted by a substituted heteroalkyl group Etc.) Polymers or similar infinite structures obtained by defining substituents are not intended to be included herein. Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, continuous substitution of a substituted aryl group with two other substituted aryl groups is limited to an aryl group substituted with (aryl substituted with (substituted aryl)). Similarly, the above definition is not intended to include disallowed substitution patterns (for example, a methyl group substituted with 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This type of disallowed substitution mode is well-known to those familiar with this technology. When used to modify chemical groups, the term "substituted" can describe other chemical groups as defined herein. Unless otherwise specified, where a group is described as optionally substituted, any substituent of the group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, and these substituents include hydroxy, halo, alkoxy, cycloalkyl, hetero Cyclic, aryl and heteroaryl. In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which One has been replaced. In other embodiments, the substituent may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is not replace. Those skilled in the art will recognize that the substituents and other parts of the compounds of the general formula herein should be selected to provide a sufficiently stable compound to provide a pharmaceutically suitable compound, which can be formulated into an acceptably stable pharmaceutical composition. Compounds with such stability are expected to fall within the scope of the present invention. Those familiar with the art should understand that any combination of the above-described definitions and substituents should not produce inoperable substances or compounds.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and Absorption delay agents and the like. The use of such media and agents as active substances in medicine is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, it is considered for use in a therapeutic composition. Supplementary active ingredients can also be incorporated into the composition.

"Solvates" are formed by the interaction of solvents and compounds. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

Combinations Patients treated by administering the IRAK4 inhibitors of the present invention often develop diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions may have inflammatory properties or may be related to cancer, metabolic disorders, gastrointestinal disorders, and the like. Therefore, one aspect of the present invention is a method for treating inflammation-related diseases or conditions or metabolic disorders, gastrointestinal disorders or cancers and the like, which method comprises administering the present to individuals in need (especially human individuals) in combination The compound of the invention and one or more compounds suitable for the treatment of such diseases.

In some embodiments, the compound of the present invention is formulated with one or more other active ingredients. In some embodiments, the other active ingredients are administered in separate dosage forms at about the same time. In some embodiments, other active ingredients are administered sequentially, and other active ingredients may be administered at different times relative to the compound of the present invention.

For example, for the combination of inflammatory diseases and conditions , the compound of the present invention can be combined with one or more of the following: 5-lipoxygenase inhibitor, acetylcholinesterase inhibitor, acetyl -CoA carboxylase (ACC) inhibitor, ACTH receptor agonist, activin receptor antagonist, acyltransferase inhibitor, corticotropin ligand, AKT1 gene inhibitor, alkaline phosphatase regulation Agents, alkaline phosphatase stimulators, androgen receptor agonists, lipoprotein C3 antagonists, ASK1 kinase inhibitors, bactericidal permeability protein stimulators, β-adrenergic receptor antagonists, β-glucuronic acid Enzyme inhibitors, B lymphocyte antigen CD20 inhibitors, bradykinin receptor modulators, BTK kinase inhibitors, calcineurin inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor modulators, cannabinoid CB2 receptors Body regulator, cannabinoid receptor antagonist, cannabinoid receptor modulator, apoptosis protease inhibitor, cathepsin S inhibitor, CCN protein stimulator, CCR3 chemokine antagonist, CCR5 chemokine antagonist, CCR9 Chemotactic hormone antagonists, CD3 modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD49b antagonists, CD49d antagonists, CD89 agonists, cell adhesion molecule inhibitors, chemokine CXC Site inhibitor, CHST15 gene inhibitor, collagen modulator, CSF-1 agonist, CSF-1 antagonist, CXC10 chemokine ligand inhibitor, CXCR2 chemokine antagonist, cyclic GMP phosphate diphosphate Esterase inhibitor, cyclooxygenase 2 inhibitor, cyclooxygenase inhibitor, cyclooxygenase stimulator, cytochrome P450 3A4 inhibitor, cytotoxic T lymphocyte protein-4 stimulator, dihydroceramide δ 4 desaturase inhibitor, dihydroorotate dehydrogenase inhibitor, DNA polymerase inhibitor, DPP-4 inhibitor, EGFR family tyrosine kinase receptor modulator, eosinophil peroxidase inhibitor , Eosin chemokine ligand inhibitor, EP4 prostaglandin receptor agonist, epidermal growth factor agonist, epidermal growth factor ligand, estrogen receptor beta agonist, factor XIII agonist, FGF -10 ligand, FGF2 receptor agonist, Fractalkine ligand inhibitor, free fatty acid receptor 2 antagonist, FXR agonist, GATA 3 transcription factor inhibitor, glucagon Peptide 1 agonist, glucocorticoid peptide 2 agonist, glucocorticoid agonist, GM-CSF receptor agonist, G protein coupled receptor 84 antagonist, guanylate cyclase receptor Agonists, histamine H2 receptor antagonists, histone acetyltransferase inhibitors, histone deacetylase inhibitors, HLA class II antigen modulators, hydrolase inhibitors, HSD17β13 inhibitors, ICAM1 gene Inhibitors, ICAM-1 inhibitors, IL1 gene inhibitors, IL-10 agonists, IL10 gene stimulators, IL-11 agonists Agent, IL-12 antagonist, IL12 gene inhibitor, IL-13 antagonist, IL-17 antagonist, IL-2 antagonist, IL-2 receptor alpha subunit inhibitor, IL-21 antagonist, IL- 23 Antagonists, IL-6 antagonists, IL6 gene inhibitors, IL-6 receptor modulators, IL-7 antagonists, IL-8 antagonists, immunoglobulin G1 agonists, immunoglobulin G2 modulators, Inosine monophosphate dehydrogenase inhibitor, insulin sensitizer, integrin α-4/β-1 antagonist, integrin α-4/β-7 antagonist, integrin α-E antagonist, integrin antagonist Agent, integrin β-7 antagonist, interferon β ligand, interleukin 17E ligand inhibitor, interleukin ligand inhibitor, interleukin receptor 17A antagonist, interleukin receptor 17B antagonist, interleukin-1 beta ligand, interleukin-1 beta ligand modulator, interleukin-6 ligand inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase Inhibitors, JAK2 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun amino terminal kinase inhibitors, LanC-like protein 2 modulators, leukotriene BLT receptor antagonists, lipoxygenase modulators, L-select Antagonist, MAdCAM inhibitor, matrix metalloproteinase inhibitor, matrix metalloproteinase modulator, melanocortin agonist, Membrane copper amine oxidase inhibitor, metalloproteinase-2 inhibitor, metal Protease-9 inhibitor, MIP 3 α ligand inhibitor, mitochondrial 10 kDa heat shock protein stimulator, monocyte differentiation antigen CD14 inhibitor, mTOR inhibitor, mucin stimulator, NAD-dependent deacetylation Sirtuin-1 stimulator, natriuretic peptide receptor C agonist, neuregulin-4 ligand, nicotinic acetylcholine receptor agonist, nicotinic ACh receptor α 4 subunit modulator , Nicotinic ACh receptor α 7 subunit stimulator, nicotinic ACh receptor β 2 subunit modulator, NK1 receptor antagonist, NKG2 D activating NK receptor antagonist, nuclear factor kappa B inhibitor, opioid Growth factor receptor agonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purine receptor agonists, p38 MAP kinase inhibitors, PARP inhibitors, PDE 4 inhibition Agents, PDGF receptor agonists, Phagocytosis stimulating peptide modulators, MurNAc phosphate pentapeptide transferase inhibitors, phospholipase A2 inhibitors, platelet activating factor receptor antagonists, potassium channel inhibitors , PPAR α agonist, PPAR δ agonist, PPAR γ agonist, protein CYR61 stimulator, protein fimH inhibitor, protein kinase C α inhibitor, protein kinase C β inhibitor, protein kinase C δ inhibitor, Egg White kinase C epsilon inhibitor, protein kinase C η inhibitor, protein kinase C theta inhibitor, protein kinase G inhibitor, protein kinase inhibitor, P-selectin glycoprotein ligand-1 inhibitor, PurH purine biosynthesis Protein inhibitors, retinoic acid receptor alpha agonists, retinoic acid receptor beta agonists, retinoid receptor agonists, RNA polymerase inhibitors, SMAD-7 inhibitors, sodium channel inhibitors , Somatostatin receptor agonist, sphingosine 1 phosphate phosphatase 1 stimulant, sphingosine 1 phosphate phosphatase modulator, sphingosine kinase 1 inhibitor, sphingosine kinase 2 Inhibitor, sphingosine-1-phosphate receptor-1 agonist, sphingosine-1-phosphate receptor-1 antagonist, sphingosine-1-phosphate receptor-1 regulation Agent, sphingosine-1-phosphate receptor-5 modulator, STAT3 gene inhibitor, STAT-3 inhibitor, STAT-4 inhibitor, stem cell antigen-1 inhibitor, superoxide dismutase modulator, Superoxide dismutase stimulator, SYK kinase inhibitor, T cell surface glycoprotein CD28 inhibitor, TGF β 1 ligand inhibitor, Thymulin agonist, THR-β agonist, TLR- 2 Antagonists, TLR-4 antagonists, TLR-9 agonists, TNF α ligand inhibitors, TNF α ligand modulators, TNF antagonists, TPL2 kinase inhibitors, clover factor modulators, pancreatic Protease inhibitors, tryptophan 5-hydroxylase inhibitors, tumor necrosis factor 14 ligand modulators, TYK2 kinase inhibitors, type I TNF receptor antagonists, type II TNF receptor modulators, non-specific growth factors Receptor modulator, vanilla extract VR1 agonist, vitamin D3 receptor agonist, Zonulin inhibitor, abatacept; acemannan; adalimumab (adalimumab); DCCT-10; apremilast; AST-120; balsalazide; balsalazide; basiliximab; beclomethasone dipropionate ); budesonide; D-9421; budesonide MMX; catridecacog; pegylated certolizumab pegol; clostridium butyricum; etanercept ( etanercept; fingolimod; glatiramer acetate; golimumab; infliximab; infliximab; infliximab biosimilar; infliximab follow-up Biological agents; interferon beta-1a; lenalido mide); mesalazine; GED-0001; AJG-501; metenkefalin acetate combined with tridecactide acetat, mycophenolate mofetil ; Naltrexone; natalizumab; nitazoxanide; olsalazine; oprelvekin; propyl-L-carnitine ; Recombinant interferon β-1a; Remestemcel-L (remestemcel-L); Rifaximin (rifaximin); Rituximab (rituximab); Ropicaine (ropivacaine); Roglie Ketones (rosiglitazone); sargramostim; secukinumab; SPD-480; tacrolimus; tamibarotene; teduglutide ; Thalidomide (thalidomide); Tocilizumab (tocilizumab); RO-4877533; Tofacitinib (tofacitinib); CP-690550; Trichuris suis ova (Trichuris suis ova); ASP-1002; Utectan Anti (ustekinumab); Valganciclovir (valganciclovir); Vedolizumab (vedolizumab); Zileuton (zileuton); Anti-CD3 imaging agent (antibody fragment, cancer/autoimmune disease), ImaginAb; AVX- 470; Cyclosporin; CXCR1/2 ligand mAb (immunology), Eli Lilly; FFP-102; GSK-3050002; INN-108; IR-777; SGM-1019; peg-Ilo-interleukin (peg- ilodecakin); PF-06480605; PF-06651600; SER-287; Syn-1002; Thetanix; Tolerant dendritic cell therapeutic agent; TOP-1288; VBY-036; VBY-129; 946414-98 -8; BMS-936557; 99mTc-phospholipid binding protein V-128; ABC-294640; abrilumab; Alequel; AMG-139; amiselimod; APD -334; ASP-3291; beclomethasone dipropionate; beltimumab (be rtilimumab); Cyclosporin; Clazakizumab; DLX-105; Docanatide; E-6011; ETX-201; FFP-104; Filgotinib; Foralumab; GED-0507-34-Levo; Givinostat; GLPG-0974; GLPG-1205; Iberogast N (ulcerative colitis), Bayer; BAY98-7410; INV-103; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; CB-01-05-MMX; LY- 3074828; mesalamine combined with N-acetylcysteine; midismase; molgramostim follow-up biologics combined with fosfomycin and carbapenem, Reponex; Multipotent adult progenitor cell therapy (ischemia/cerebral palsy), Athersys/Healios; NN-8828; Onochimab (olokizumab); OvaSave; P-28-GST; PDA-002; PF- 4236921; PF-547659; prednisolone; PUR-0110; QBECO; RBX-2660; modified naltrexone; JKB-122; SB-012; sotrastaurin; STNM-01; TAK -114; tetomilast; Debio-0512; TRK-170; TRX-318; vatelizumab; VB-201; ZP-1848; zucapsaicin; ABT -494; alicaforsen; Ampion; BI-655066; briakinumab; cannabidiol; carotegast methyl; cobitoli Cobitolimod; dexamethasone sodium phosphate; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02; meserazine; A Metronidazole mongersen (metronidazole mongersen); octizumab (oc relizumab; ozanimod; peficitinib; RHB-104; rifaximin; tildrakizumab; tralokinumab; brodazan Brodalumab; laquinimod; plecanatide; telotristat etiprate; infliximab biosimilar, Samsung Bioepis; AZD-058; and rifle Butin (rifabutin) combined with clarithromycin (clarithromycin) and further combined with clofazimine (clofazimine).

In addition, the following non-exhaustive list of compound classes and compounds can be combined with the compounds of the present invention: 5-lipoxygenase inhibitors, such as zileuton, etalocibm FPL-64170, E-3040, and BU- 4601A; Acetylcholinesterase inhibitors, such as BL-7040; ACTH receptor agonists, such as mitphaline acetate in combination with Tridexide acetate and FAR-404; activin receptor antagonists, such as follicles Stastatin; glycyltransferase inhibitors, such as AZD-0585; adrenocorticotropic hormone ligands, such as mitphaline acetate in combination with tridecathed acetate and FAR-404; AKT1 gene inhibitors, such as vidolidine (vidofludimus); alkaline phosphatase modulators, such as recombinant human alkaline phosphatase (oral, ulcerative colitis), AM-Pharma; alkaline phosphatase stimulators, such as bovine alkaline phosphatase; androgen receptor promoting Effective agents, such as PB-005; lipoprotein C3 antagonists, such as AZD-0585; bactericidal permeability protein stimulators, such as opebacan; β-adrenergic receptor antagonists, such as NM-001; β-glucuronidase inhibitors, such as KD-018; B lymphocyte antigen CD20 inhibitors, such as octuzumab, rituximab; bradykinin receptor modulators, such as gemvenostat; calcium regulation Neurophosphatase inhibitors, such as tacrolimus, cyclosporine; calcium channel inhibitors, such as clotrimazole; cannabinoid CB1 receptor modulators, such as GWP42003-P, cannabidiol; cannabinoid CB2 Receptor modulators, such as GWP42003-P, cannabidiol; cannabinoid receptor antagonists, such as fingolimod; cannabinoid receptor modulators, such as GWP42003-P, cannabidiol; cathepsin S inhibitors, such as VBY-129, VBY-036; CCN protein stimulators, such as CSA-13; CCR3 chemokine antagonists, such as bertilimumab; CCR5 chemokine antagonists, such as HGS-1025; CCR9 chemokine antagonists , Such as MLN-3126, vercirnon, CCX-025; CD3 modulators, such as vecilizumab; CD40 ligand inhibitors, such as FFP-104; CD40 ligand receptor antagonists, such as FFP-104, FFP-102, tocilizumab; CD49b antagonists, such as veterizumab; CD49d antagonists, such as ELND-004; CD89 agonists, such as HF-1020; cell adhesion molecule inhibitors, Such as natalizumab, alicaversen (intravenous), ASP-2002, ISIS-2302; chemokine CXC ligand inhibitors, such as CXCR1/2 ligand mAb (immunology), Eli Lilly; CHST15 Gene inhibitors, such as STNM-0 1. Collagen modulators, such as fat-derived stem cell therapeutics (Celution system), Cytori, DCCT-10; CSF-1 agonists, such as sargramostim, Morastine follow-up biologics Combining fosfomycin and carbapenem (intestinal, Crohn's disease), Reponex; CSF-1 antagonist, such as JNJ-40346527; CXC10 chemotactic hormone ligand inhibitor, such as 946414-98-8, BMS- 936557; CXCR2 chemokine antagonists, such as elubrixin; cyclic GMP phosphodiesterase inhibitors, such as CEL-031; cyclooxygenase 2 inhibitors, such as P-54; cyclooxygenase Inhibitors, such as meserazine, sodium 4-aminosalicylate, AJG-501, AGI-022; cyclooxygenase stimulators, such as nicotine polacrilex; cytochrome P450 3A4 inhibitors, such as KD-018; Cytotoxic T lymphocyte protein-4 stimulators, such as Abatacept; Dihydroceramide delta 4 desaturase inhibitors, such as ABC-294640; Dihydroorotate dehydrogenase inhibitors, such as Vedolidine; DNA polymerase inhibitors, such as valganciclovir; EGFR family tyrosine kinase receptor modulators, such as neuregulin 4 (Crohn's disease/ulcerative colitis/necrotizing enterocolitis), Avexegen therapy/Children's Hospital of Los Angeles; eosinophil peroxidase inhibitors, such as AWEPOPD-01, AWEPO-003; eosin ligand inhibitors, such as bertilimumab; EP4 Prostaglandin receptor agonists, such as KAG-308; epidermal growth factor agonists, such as heparin EGF-like factor, Scios Nova; epidermal growth factor ligands, such as Hebervis; estrogen receptor beta Agonists, such as prinaberel; factor XIII agonists, such as capridine; FGF-10 ligands, such as repifermin; FGF2 receptor agonists, such as F2A; Frattaquet ligand inhibitors, such as E-6011; free fatty acid receptor 2 antagonists, such as GLPG-0974; GATA 3 transcription factor inhibitors, such as SB-012; glycogen-like peptide 2 agonists, Such as Teduglutide, ZP-1848, NB-1002; Glucocorticoid agonists such as budesonide, beclomethasone dipropionate, dexamethasone sodium phosphate, AJG-511, DOR-201, D-9421 -C; GM-CSF receptor agonists, such as sargramostim, morastine follow-up biologics combined with fosfomycin combined with carbapenem (intestinal, Crohn’s disease), Reponex; G protein coupled receptor Body 84 Antagonists, such as GLPG-1205; guanylate cyclase receptor agonists, such as docanalide, SP-333; histamine H2 receptor antagonists, such as bismuth, Medeva; histone acetyltransferase Inhibitors, such as TIP60 inhibitors (ulcerative colitis/inflammatory bowel disease/autoimmune diseases), University of Pennsylvania; histone deacetylase inhibitors, such as gemvenostat; HLA Class II antigen modulators, such as HLA class II protein modulators (Crohn's disease), Nextera AS; hydrolase inhibitors, such as SC-56938; ICAM1 gene inhibitors, such as Alicarverson; ICAM-1 inhibitors , Such as Alika Verson (intravenous), ISIS-2302; IL1 gene inhibitors, such as PLR-14; IL-10 agonists, such as peg-IL, AM-0010; IL10 gene stimulators, such as gene Therapeutic agent (IL-10), British Institute of Technology (Imperial College); IL-11 agonist, such as oprel, YM-294; IL-12 antagonist, such as ustekinumab, bevac Lizumab, apilimod; IL12 gene inhibitors, such as RDP-58; IL-13 antagonists, such as tarotinumab, anrukinzumab; IL-17 antagonists, Such as secukinumab, vedoludil; IL-2 antagonists, such as daclizumab (daclizumab); IL-2 receptor α subunit inhibitors, such as basiliximab, daclizumab, BSX -003, Ro-34-7375; IL-21 antagonist, such as NN-8828, ATR-107; IL-23 antagonist, such as tizumab, ustekinumab, BI-655066, AMG-139 , Bevacizumab, LY-3074828, apyrimod; IL-6 antagonists, such as tocilizumab, clezanizumab, onokizumab, HMPL-004, AMG-220, FM -101; IL6 gene inhibitors, such as YSIL6-T-PS; IL-6 receptor modulators, such as tocilizumab; IL-7 antagonists, such as interleukin-7 receptor modulators (ulcerative colitis /T cell acute lymphoblastic leukemia), Effimune; IL-8 antagonists, such as oxalixin, clotrimazole; immunoglobulin G1 agonists, such as HF-1020; immunoglobulin G2 modulators, such as PF-547659; Inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil; Insulin sensitizers, such as oxrafenol, rosiglitazone, HE-3286, EGS-21; Integrin α -4/β-1 antagonist, such as natalizumab, TRK-170, firategrast; integration Α-4/β-7 antagonists, such as etolizumab, vedolizumab, abrizumab, methylcarotester, TRK-170, felamlast; integrin α- E antagonists, such as idolizumab; integrin antagonists, such as vitelizumab, ASP-2002; integrin beta-7 antagonists, such as idolizumab; interferon beta ligand, Such as interferon β-1a, recombinant interferon β-1a, Serono; interleukin 17E ligand inhibitors, such as anti-IL-17BR humanized antibodies (pulmonary fibrosis/asthma/ulcerative colitis), medical research Committee Technology (Medical Research Council Technology); interleukin ligand inhibitors, such as HE-3286; interleukin receptor 17A antagonists, such as bridalumab; interleukin receptor 17B antagonists, such as anti IL-17BR humanized antibody (pulmonary fibrosis/asthma/ulcerative colitis), medical research committee technology; interleukin-1 beta ligand, such as K(D)PT, PUR-0110, HMPL-004; mediation Interleukin-1 beta ligand modulators, such as PUR-0110, HMPL-004; interleukin-6 ligand inhibitors, such as PF-4236921; JAK tyrosine kinase inhibitors, such as tofacitinib, Pifitinib; Jak1 tyrosine kinase inhibitors, such as ABT-494, Tofacitinib, Fegotinib, Pifitinib, GLPG-0555, Sositinib; JAK2 gene inhibitors, such as Vido Ludi; Jak3 tyrosine kinase inhibitors, such as Tofacitinib, Pifitinib; Jun amino terminal kinase inhibitors, such as Symomod; LanC-like protein 2 modulators, such as BT-11; Leukotrienes BLT receptor antagonists, such as ONO-4057, etalotz, SC-53228, SC-52798; lipoxygenase modulators, such as meserazine; L-selectin antagonists, such as BNP-001; MAdCAM inhibition Agents, such as vedolizumab, PF-547659; matrix metalloproteinase inhibitors, such as D-5410; matrix metalloproteinase modulators, such as D-5410; melanocortin agonists, such as ASP-3291; copper amine Oxidase inhibitors, such as vepalimomab; metalloproteinase-2 inhibitors, such as KD-018, RWJ-68354; metalloproteinase-9 inhibitors, such as GS-5745; MIP 3 α ligand inhibition Agents, such as GSK-3050002; mitochondrial 10 kDa heat shock protein stimulators, such as INV-103; monocyte differentiation antigen CD14 inhibitors, such as CD14 anti-inflammatory agents, Cornell; mTOR inhibitors, such as P-2281; Protein stimulants, such as rebamipide; NAD-dependent deacetylase sirtuin-1 stimulants, various Such as SRT-2104; natriuretic peptide receptor C agonist, such as pukanatide; neuregulin-4 ligand, such as neuregulin 4 (Crohn's disease/ulcerative colitis/necrotizing enterocolitis ), Avexegen therapy/Los Angeles Children's Hospital; Nicotine acetylcholine receptor agonists, such as TC-2403, nicotine lozenge, nicotine; Nicotine ACh receptor α 4 subunit modulators, such as TC-2403 ; Nicotinic ACh receptor α 7 subunit stimulators, such as GTS-21; nicotinic ACh receptor β 2 subunit modulators, such as TC-2403; NK1 receptor antagonists, such as KD-018, benzene sulphonopir Tanammonium; NKG2 D activating NK receptor antagonist, such as NNC-0142-002; nuclear factor kappa B inhibitors, such as KD-018, Compitolimole, CSA-13, HE-3286, HMPL-004, Ai Rela (Avrina), meserazine combined with N-Acetylcysteine, P-54; opioid growth factor receptor agonists, such as mitphaline acetate combined with tridecated acetate, FAR-404 ; Opioid receptor antagonists, such as naltrexone, IRT-103; opioid receptor delta antagonists, such as KD-018; oxidoreductase inhibitors, such as oseperazine; P2X7 purinoceptor agonists, such as Givenostat; p38 MAP kinase inhibitors, such as RDP-58, doramapimod, Semomod, RWJ-68354; PARP inhibitors, such as EB-47, INO-1003; PDE 4 inhibitors , Such as apramilast, tetomilast, CC-1088; PDGF receptor agonists, such as oprin, YM-294; phagocytosis stimulating peptide modulators, such as 99mTc-RP-128; MurNAc phosphate pentapeptide transferase inhibitors, such as SQ-641; Phospholipase A2 inhibitors, such as varespladib methyl; platelet activating factor receptor antagonists, such as dersalazine sodium ; Potassium channel inhibitors, such as clotrimazole; PPAR α agonists, such as oxafenol (GFT-1007); PPAR δ agonists, such as oxafenol (GFT-1007); PPAR γ agonists , Such as rosiglitazone, GED-0507-34-Levo, etalotz; protein CYR61 stimulators, such as CSA-13; protein fimH inhibitors, such as EB-8018; protein kinase C α inhibitors, such as Sota Tolin (AEB-071); Protein kinase C β inhibitors, such as Sotatalolin (AEB-071); Protein kinase C δ inhibitors, such as Sotatalolin (AEB-071); Protein kinase C epsilon inhibitors , Such as Sotatoline (AEB-071); protein kinase C η inhibitors, such as Sotatoline (AEB-07 1); protein kinase C θ inhibitors, such as Sotatalin (AEB-071); protein kinase G inhibitors, such as CEL-031; protein kinase inhibitors, such as TOP-1288; P-selectin glycoprotein coordination Body-1 inhibitors, such as SEL-K2; PurH purine biosynthetic protein inhibitors, such as mycophenolate mofetil; Retinoic acid receptor alpha agonists, such as Tamibarotene; Retinoic acid receptor Beta agonists, such as Tamibarotene; Retinoid receptor agonists, such as Tamibarotene; RNA polymerase inhibitors, such as Rifaximin; SMAD-7 inhibitors, such as Mogo Sen (GED-0301); sodium channel inhibitors, such as ropivacaine; somatostatin receptor agonists, such as vaprastatide; sphingosine 1 phosphate phosphatase 1 stimulators, such as APD-334; Sphingosine 1 phosphate phosphatase modulators, such as S1P modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoid arthritis), Akaal Pharma; sphingosine kinase 1 inhibitors, such as ABC- 294640; sphingosine kinase 2 inhibitors, such as ABC-294640; sphingosine-1-phosphate receptor-1 agonists, such as ozanimol (RPC-1063), KRP-203; nerve sheath Sphingosine-1-phosphate receptor-1 antagonists, such as amislimol (MT-1303); sphingosine-1-phosphate receptor-1 modulators, such as fingolimod (FTY- 720), ozanimol (RPC-1063), amislimol (MT-1303); sphingosine-1-phosphate receptor-5 modulators, such as ozanimol; STAT3 gene inhibitor STAT-3 inhibitors, such as TAK-114; STAT-4 inhibitors, such as STAT-4 antisense oligonucleotides (Crohn’s disease/colitis), NIAID; stem cell antigen-1 Inhibitors, such as amopine, DMI-9523; superoxide dismutase modulators, such as Midisimath, LT-0011; superoxide dismutase stimulators, such as superoxide dismutase; T cell surface sugar Protein CD28 inhibitors, such as Abatacept; TGF β 1 ligand inhibitors, such as Mogosen, GED-0301; Thymonona peptide agonists, such as Syn-1002; TLR-2 antagonists, such as VB-201 ; TLR-4 antagonists, such as JKB-122, VB-201; TLR-9 agonists, such as BL-7040, Compatolimole; TNF α ligand inhibitors, such as Adalimumab, polyethylene two Alcoholized Certuzumab, Infliximab Biosimilar, Infliximab, Golimumab, ISIS-104838, CSA-13, DLX-105, Adalimumab Biosimilar, Deserazine Sodium , Debio-0512, HMPL-004, DLX-105, Infliximab follow-up biologics, AZD-9773, CYT-020-TNFQb, DOM-0200; TNFα ligand modulators, such as PUR-0110, CDP-571; TNF antagonists, such as Etanercept, Pegylated Certuzumab, AVX-470 , Onercept (onercept); Clover factor modulators, such as AG-012; Tryptase inhibitors, such as APC-2059; Tryptophan 5-hydroxylase inhibitors, such as Trostanoxoplast; Tumor necrosis factor 14 ligand modulators, such as SAR-252067; type I TNF receptor antagonists, such as DOM-0100; type II TNF receptor modulators, such as etanercept; non-specific growth factor receptor modulators , Such as AP-005; vanilla extract VR1 agonists, such as Zhucasexin; vitamin D3 receptor agonists, such as calcitriol (calcitriol); and zonulin inhibitors, such as larizolate acetate, AT-1001.

In addition, the following non-exhaustive list of compound categories and compounds can be combined with the compounds of the present invention: 14-3-3 protein η inhibitors, 5-lipoxygenase inhibitors, Abl tyrosine kinase inhibitors, ACTH receptor promoters Effective agent, adenosine A3 receptor agonist, adenosine deaminase inhibitor, ADP ribosyl cyclase-1 modulator, ADP ribosylation factor 6 inhibitor, ACTH ligand, polyprotein Glycanase-2 inhibitors, albumin modulators, AP1 transcription factor inhibitors, basic immunoglobulin inhibitors, Bcr protein inhibitors, B lymphocyte antigen CD19 inhibitors, B lymphocyte antigen CD20 inhibitors, B lymphocytes Antigen CD20 modulator, B lymphocyte stimulator ligand inhibitor, bradykinin receptor modulator, BRAF gene inhibitor, branched chain amino acid aminotransferase 1 inhibitor, bromine-containing domain protein inhibitor, Btk Tyrosine kinase inhibitor, cadherin-11 antagonist, calcineurin inhibitor, calcium channel inhibitor, carbonic anhydrase inhibitor, cathepsin K inhibitor, cathepsin S inhibitor, CCR1 chemotactic hormone Antagonist, CCR2 chemokine antagonist, CCR3 gene modulator, CCR5 chemokine antagonist, CD126 antagonist, CD29 modulator, CD3 modulator, CD39 agonist, CD4 agonist, CD4 antagonist, CD40 Locus inhibitor, CD40 ligand receptor antagonist, CD40 ligand receptor modulator, CD52 antagonist, CD73 agonist, CD79b modulator, CD80 antagonist, CD86 antagonist, CD95 antagonist, cell adhesion Molecular inhibitors, choline kinase inhibitors, cluster hormone stimulators, complement C5 factor inhibitors, complement factor stimulators, C-reactive protein inhibitors, CSF-1 antagonists, CXC10 chemotactic hormone ligand inhibitors, CXCR4 chemotactic Cyclin antagonist, cyclin-dependent kinase inhibitor 1 inhibitor, cyclin-dependent kinase-2 inhibitor, cyclin-dependent kinase-4 inhibitor, cyclin-dependent kinase-5 inhibitor, cyclin-dependent Kinase-6 inhibitor, cyclin-dependent kinase-7 inhibitor, cyclin-dependent kinase-9 inhibitor, cyclooxygenase 2 inhibitor, cyclooxygenase 2 modulator, cyclooxygenase inhibitor, cytokine Solute phospholipase A2 inhibitor, cytotoxic T lymphocyte protein-4 modulator, cytotoxic T lymphocyte protein-4 stimulator, DHFR inhibitor, diamine acetyltransferase inhibitor, dihydroorotate dehydrogenation Enzyme inhibitor, elongation factor 2 inhibitor, eosin 2 ligand inhibitor, EP4 prostaglandin receptor antagonist, erythropoietin receptor agonist, Fas ligand, FGF-2 ligand inhibition Agent, FK506 binding protein-12 modulator, folate antagonist, folate receptor agonist, folate receptor beta antagonist, folate receptor modulator, fratake ligand inhibitor, Fyn tyrosine kinase inhibitor Agent, G protein coupled receptor 15 antagonist, GABA A receptor modulator, glucocorticoid agonist , Glucocorticoid antagonist, glucocorticoid-induced leucine zipper stimulator, GM-CSF ligand inhibitor, GM-CSF receptor antagonist, GM-CSF receptor modulator, growth regulatory protein alpha coordination Body inhibitor, Hwith Kwith ATPase inhibitor, histamine H4 receptor antagonist, histone deacetylase inhibitor, histone deacetylase-6 inhibitor, HIV-1 gp120 protein inhibitor, HLA Class II antigen DQ-2 α modulator, HLA class II antigen inhibitor, HLA class II antigen modulator, Hsp 70 family inhibitor, hypoxia inducible factor-1 inhibitor, IFNB gene stimulator, I-κB kinase β Inhibitors, I-κB kinase inhibitors, IL-1 antagonists, IL-10 agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL -17 receptor modulator, IL-2 agonist, IL-2 antagonist, IL-21 antagonist, IL-23 antagonist, IL-3 antagonist, IL-4 agonist, IL-6 antagonist , IL-6 receptor modulator, immunoglobulin antagonist, immunoglobulin G1 agonist, immunoglobulin G1 antagonist, immunoglobulin G1 modulator, immunoglobulin G2 antagonist, immunoglobulin G2 modulator , Immunoglobulin γ Fc receptor II modulator, immunoglobulin γ Fc receptor IIB antagonist, immunoglobulin κ modulator, immunoglobulin M antagonist, inducible nitric oxide synthase inhibitor, inosine monophosphate Dehydrogenase inhibitor, insulin sensitizer, integrin α-1/β-1 antagonist, integrin α-4/β-1 antagonist, integrin antagonist, interferon β ligand, interferon γ Ligand, interleukin 17A ligand inhibitor, interleukin 17F ligand inhibitor, interleukin 23A inhibitor, interleukin ligand, interleukin receptor 17A antagonist, interleukin -1 β ligand inhibitor, interleukin-10 ligand, interleukin-2 ligand, interleukin-4 ligand, interleukin-6 ligand inhibitor, Itk tyramine Acid kinase inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak2 tyrosine kinase inhibitor, JAK3 gene inhibitor, Jak3 tyrosine kinase inhibitor, Jun amino terminal kinase inhibitor, KCNA voltage-gated potassium channel-3 modulator, Kelch-like ECH-related protein 1 modulator, Kit tyrosine kinase inhibitor, LanC-like protein 2 modulator, LITAF gene inhibitor, lymphocyte function antigen-3 receptor antagonist , Lyn tyrosine kinase inhibitor, macrophage mannose receptor 1 modulator, MAdCAM inhibitor, MAP kinase modulator, MAP3K2 gene inhibitor, MAPKAPK5 inhibitor, matrix metalloproteinase inhibitor, MCL1 gene inhibitor, MEK Protein kinase inhibitor, MEK-1 protein kinase inhibitor, MEK-2 protein kinase inhibitor, membrane copper amine oxygen Chemical enzyme inhibitor, metalloproteinase-2 inhibitor, metalloproteinase-9 inhibitor, midkine ligand inhibitor, mitochondrial 10 kDa heat shock protein stimulator, mTOR complex 1 inhibitor, mTOR inhibitor, NAD ADP ribosyltransferase stimulator, NAMPT gene inhibitor, NF κB inhibitor stimulator, NFAT gene inhibitor, NFE2L2 gene stimulator, nicotinic acetylcholine receptor antagonist, NK cell receptor modulator, NKG2 AB activating NK receptor antagonist, NKG2 D activating NK receptor antagonist, nuclear erythrocyte 2 related factor 2 stimulator, nuclear factor kappa B inhibitor, nuclear factor kappa B modulator, nuclear factor kappa B p105 inhibitor , Opioid growth factor receptor agonist, opioid receptor delta antagonist, osteoclast differentiation factor antagonist, osteoclast differentiation factor ligand inhibitor, oxidoreductase inhibitor, P2X7 purine receptor agonist Agent, p38 MAP kinase α inhibitor, p38 MAP kinase inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor agonist, PDGF receptor antagonist, PDGF-B ligand inhibitor, PERK gene inhibitor Agent, phosphoinositide-3 kinase δ inhibitor, phosphoinositide-3 kinase γ inhibitor, phospholipase A2 inhibitor, platelet activating factor receptor antagonist, PPAR γ agonist, programmed cell death protein 1 regulation Agent, prostaglandin D synthetase stimulator, protein arginine deiminase inhibitor, protein tyrosine kinase inhibitor, PurH purine biosynthetic protein inhibitor, Rho-related protein kinase 2 inhibitor, separation enzyme (Seprase) Inhibitors, signal transduction protein CD24 modulators, signal transduction inhibitors, sodium glucose transporter-2 inhibitors, sphingosine 1 phosphate phosphatase modulators, STAT3 gene inhibitors, superoxide dismutase stimulators , SYK family tyrosine kinase inhibitor, Syk tyrosine kinase inhibitor, Syndecan-1 inhibitor, T cell receptor antagonist, T cell receptor modulator, T cell surface sugar Protein CD28 inhibitor, T cell surface glycoprotein CD28 stimulator, TAK1 binding protein modulator, Talin modulator, T cell differentiation antigen CD6 inhibitor, T cell surface glycoprotein CD8 inhibitor, Tenascin (Tenascin) Modulator, TGF β agonist, Thymulin agonist, TLR-2 antagonist, TLR-4 antagonist, TLR-9 antagonist, TNF α ligand inhibitor, TNF α ligand Modulators, TNF antagonists, TNF gene inhibitors, TNF receptor modulators, TNFSF11 gene inhibitors, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin modulators, tumor necrosis factor 13C receptor antagonists, Tumor Necrosis Factor 15 Ligand Inhibitor, Tumor Necrosis Factor Ligand 13 Inhibitor, Tumor Tumor necrosis factor ligand inhibitor, type I IL-1 receptor antagonist, type I TNF receptor antagonist, type II TNF receptor modulator, non-specific GPCR agonist, VEGF receptor antagonist, VEGF- 2 Receptor antagonist, VEGF-2 receptor modulator, VEGF-B ligand inhibitor, apoptosis protein X sex-linked inhibitor inhibitor, Zap70 tyrosine kinase inhibitor, 99mTc labeled phospholipid binding protein V -128, abatacept, abatacept biosimilars, ABBV-257, ABT-122, ABT-494, acalabrutinib, aceclofenac, actarit ), MS-392, adalimumab, adalimumab biosimilars, adalimumab follow-up biological preparations, AK-106, ALX-0061, aminopterin, anakinra, a Nakinra's biosimilar drugs, Anakinra's follow-up biologics, ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064, Bimei Bimekizumab, BiP (Rheumatoid Arthritis) (Kings College London), BLHP-006, Blisibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, canakinumab, Cartistem, CCX-354, CD24-IgFc, celecoxib, cerdulatinib, pegylated cerdulatinib Monoclonal antibody, CF-101, CFZ-533, CHR-5154, cibinetide, cyclosporine, clezanizumab, CNTO-6785, corticotropin (Mallinckrodt), CR-6086, CreaVax-RA, CWG-92, CWG-940, Cx-611, DE-098, deflazacort, Rheumavax, denosumab, diacerein ), diclofenac, E-6011, eicosapentaenoic acid monoglyceride, etanercept, etanercept biosimilar, etanercept follow-up biological preparation, etodolac, Etacoxib (etoricoxib), figotinib, fosdagrocorat, gerilizumab (gerilimzumab), ginsenoside CK, gemvenota, goat multi-strain antibody, ge Lilimumab, GS-5745, GS-9876, GSK-3196165, HM-71224, HMPL-523, sodium hyaluronate, IB-RA (injectable, rheumatoid arthritis) (Innobioscience), IB-RA (Oral, rheumatoid arthritis) (Innobioscience), iguratimod, IMD-2560, imidazole salicylate, infliximab, infliximab biologically better drug, Yingli Xiximab biosimilars, INSIX RA, interferon gamma follow-up biologics, interleukin-2 (injectable), interleukin-2 follow-up biologics, INV-103, IR-501, Etolizumab, JNJ-40346527, Ka Shu Ning, KD-025, Ketoprofen combined with omeprazole, leflunomide, lenzilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib, mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methylamine Methotrexate, MGD-010, misoprostol combined with diclofenac, MM-A01-01, monalizumab, MORAb-022, MPC-300-IV, MRC-375, naphthalene Nabumetone, namilumab, naproxen combined with esomeprazole, naproxen combined with esomeprazole strontium, ocaratuzumab ), ofatumumab (ofatumumab), OHR-118, Onochimab, OM-89, once a day naproxen (oral controlled release, pain) (Alvogen), ONO-4059 (Oralgam), Orly Ozoralizumab, pifitinib, pelubiprofen, PF-06687234, piperidone hydrochloridum, piroxicam, prednisone, prednisone , Prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, Rabeximod, RCT-18, recombinant human CD22 monoclonal antibody (Intravenous infusion) (Lonn Ryonn Pharma/SinoMab Bioscience (Shenzhen)), recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis) (Shanghai Fudan, Zhangjiang Bio-Pharmaceutical), recombinant human interleukin -2 Recombinant TNF receptor 2-Fc fusion protein mutant, RG-6125, RhuDex, rifabutin combined with clarithromycin combined with clofazimin, rituximab, rituximab biosimilars, rituximab Tuximab follow-up biologics, RPI-78, SAN-300, sarilumab, SBI-087, seliciclib, SHR-0302, sirukumab, Spebrutinib, SSS-07, KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079, tarenflurbil ) (Transdermal spray, skin disease/rheumatoid arthritis) (MIKA Pharma/GALENpharma), Tc 99m tilmanocept, Tc [99Tc] methylene bisphosphonate, tenoxicam ( tenoxicam), Debio-0512, tocilizumab, tofacitinib, pig whipworm eggs, umbilical cord-derived leaf cell stem cells (intravenous, RA/liver disease) (Alliancells/Zhongyuan Union), ustekinumab, VAY-736, VB-201, WF-10, XmAb-5871, YHB-1411-2; 14-3-3 protein η inhibitors, such as anti-AGX-020 mAbs (rheumatoid arthritis), Augurex; 5- Lipoxygenase inhibitors, such as tenoxicam, darbufelone, tebufelone, licofelone, ZD-2138, etalotz, tenidap ( tenidap), tepoxalin, flobufen, SKF-86002, PGV-20229, L-708780, WY-28342, T-0757, T-0799, ZM-216800, L-699333, BU 4601A, SKF-104351, CI-986; Abl tyrosine kinase inhibitors, such as imatinib; ACTH receptor agonists, such as FAR-404, mitphaline acetate combined with tridecatide acetate Germany; adenosine A3 receptor agonists, such as CF-101; adenosine deaminase inhibitors, such as cladribine (cladrib ine), pentostatin, FR-221647; ADP ribosyl cyclase-1 modulators, such as indatuximab, ravtansine; ADP ribosylation factor 6 inhibitor , Such as NAV-2729; adrenocorticotropin ligands, such as corticotropin (Mallinckrodt), FAR-404, mitphaline acetate combined with triidekateide acetate; proteoglycanase-2 inhibitors, such as GIBH-R-001-2; Albumin modulators, such as ALX-0061, ONS-1210; AP1 transcription factor inhibitors, such as T-5224, Talunfobi, SP-10030; Basic immunoglobulin inhibitors, such as ERG-240; Bcr protein inhibitors, such as imatinib; B lymphocyte antigen CD19 inhibitors, such as XmAb-5871, MDX-1342; B lymphocyte antigen CD20 inhibitors, such as octizumab, ovatumumab , Rituximab, rituximab biosimilars, vitolizumab, rituximab follow-up biological preparations, ocalabizumab, BLX-301, IDEC-102, ABP-798, GP -2013, MK-8808, HLX-01, CT-P10, TL-011, PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101; B lymphocytes Antigen CD20 modulators, such as rituximab biosimilars, SBI-087, TRU-015, DXL-625; B lymphocyte stimulator ligand inhibitors, such as belimumab, RCT-18 , Brimod, tabalumab, atacicept, briobacept; bradykinin receptor modulators, such as gemvenostat; BRAF gene inhibitors, such as Binimetinib; branched chain amino acid aminotransferase 1 inhibitors, such as ERG-240; bromine-containing protein inhibitors, such as RVX-297, ZEN-003694; Btk tyrosine kinase inhibitor, Such as acalabrutinib, HM-71224, sbybrutinib, BTK inhibitor (rheumatoid arthritis) (Humanwell Healthcare/Wuxi AppTech), BMS-986142, TAK-020, ONO-4059, TAS- 5315, ABBV-105, AC-0025, RN-486, CG-026806, GDC-0834; Cadherin-11 antagonists, such as RG-6125; calcineurin inhibitors, such as HS-378, cyclosporine Bacteria; calcium channel inhibitors, such as RP-3128; Carbonic anhydrase inhibitors, such as polmacoxib; Cathepsin K inhibitors, such as CRA-013783, T-5224, AM-3876, VEL-0230, NPI-2019; Cathepsin S inhibition Agents, such as MIV-247, AM-3876, RWJ-445380, NPI-2019; CCR1 chemokine antagonists, such as BX-471, BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897 , CP-481715, PS-375179; CCR2 chemokine antagonists, such as MK-0812, AZD-6942; CCR3 gene modulators, such as CM-102; CCR5 chemokine antagonists, such as maraviroc , OHR-118, NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists, such as sareluzumab; CD29 modulators, such as PF-06687234; CD3 modulators, such as otelixizumab (otelixizumab) ; CD39 agonists, such as AAV5-CD39/CD73 (rheumatoid arthritis), Arthrogen; CD4 agonists, such as Maravir; CD4 antagonists, such as tregalizumab (tregalizumab), zamudan Anti (zanolimumab), MTRX-1011A, BW-4162W94, EP-1645, cleximab (clenoliximab); CD40 ligand inhibitors, such as pegylated dapilizumab (dapirolizumab pegol); CD40 Position receptor antagonists, such as BI-655064, anti-CD40-XTEN, teneliximab; CD40 ligand receptor modulators, such as CFZ-533; CD52 antagonists, such as alemtuzumab ( alemtuzumab); CD73 agonists, such as AAV5-CD39/CD73 (rheumatoid arthritis), Arthrogen; CD79b modulators, such as MGD-010; CD80 antagonists, such as RhuDex, XENP-9523, ASP-2408, Abbas Generic better drugs; CD86 antagonists, such as ES-210, Abatacept better drugs, ASP-2408, XENP-9523; CD95 antagonists, such as DE-098, CS-9507; cell adhesion molecule inhibitors, Such as natalizumab (natalizumab), alikaversen, NPC-17923, TK-280, PD-144795; choline kinase inhibitors, such as choline kinase inhibitors (rheumatoid arthritis), UC San Die go; clusterin stimulants, such as alemtuzumab; complement C5 factor inhibitors, such as eculizumab, antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center (Leiden University Medical Center); complement factor stimulators, such as CM-101; C-reactive protein inhibitors, such as IB-RA (oral, rheumatoid arthritis) (Innobioscience), ISIS-353512; CSF-1 antagonists, such as Marseille Tinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578, PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors, such as 946414-98-8, BMS- 936557; CXCR4 chemokine antagonists, such as plexafor (plerixafor); cyclin-dependent kinase inhibitor 1 inhibitors, such as CDK-1/2/5/7/9 inhibitors (cancer/tumorigenesis/class Rheumatoid arthritis), BioPatterns; Cyclin-dependent kinase-2 inhibitors, such as Selihib, BP-14; Cyclin-dependent kinase-4 inhibitors, such as CDK-4/6 inhibitors (rheumatoid Arthritis), Teijin; Cyclin-dependent kinase-5 inhibitor, such as BP-14; Cyclin-dependent kinase-6 inhibitor, such as CDK-4/6 inhibitor (rheumatoid arthritis), Teijin; Cycle Cyclin-dependent kinase-7 inhibitors, such as BP-14, Selihib; Cyclin-dependent kinase-9 inhibitors, such as BP-14, Selihib; cyclooxygenase 2 inhibitors, such as Sene Coxib, etacoxib, premex, laflunimus, etodolac, meloxicam, IB-RA (injectable, rheumatoid arthritis) (Innobioscience), IB-RA (Oral, rheumatoid arthritis) (Innobioscience), SKLB-023, meloxicam, lumiroco; cyclooxygenase 2 modulators, such as DRGT-46; cyclooxygenase inhibitors, such as acetochlor Fenac, diclofenac, imidazole salicylate, naproxcinod, naproxen etemesil, misoprostol combined with diclofenac, nabumetone, naproxen combined with esomera Azole, naproxen combined with esomeprazole strontium, naproxen once a day (oral controlled release, pain) (Alvogen), pipelusifene, LY-210073, tenoxicam, ricoferone, NS- 398, bromfenac, L-746483, LY-255283, tenidap, tepoxalin, flurobufen, ibuprofen, flurbiprofen (flurbiprofen), SKF-86002, SC-57666, WY-28342, CI-986, bermoprofen; cytosolic phospholipase A2 inhibitors, such as AVX-002; cytotoxic T lymphocyte protein-4 regulation Agents, such as belacept (belatacept), ES-210; cytotoxic T lymphocyte protein-4 stimulators, such as abatacept, abatacept biosimilars, BMS-188667; DHFR inhibitors, such as methamphetamine MPI-2505, MBP-Y003; diamine acetyltransferase inhibitors, such as diminazene aceturate; dihydroorotate dehydrogenase inhibitors, such as DHODH inhibitors (rheumatoid arthritis) /Autoimmune diseases) (East China University of Science and Technology), ASLAN-003, Lafluolimus, Leflunomide, HWA-486, ABR-224050; Elongation factor 2 inhibitors, such as Ang Denileukin diftitox; Eosin 2 ligand inhibitors, such as CM-102; EP4 prostaglandin receptor antagonists, such as CR-6086; Erythropoietin receptor agonists, such as Sibinene Fas ligands, such as AP-300; FGF-2 ligand inhibitors, such as RBM-007; FK506 binding protein-12 modulators, such as temsirolimus; folic acid antagonists, such as methamphetamine Folic acid receptor agonists, such as folate receptor modulators (chimeric protein, cancer/rheumatoid arthritis), Proda Biotech; folate receptor modulators, such as tyc (99mTc) Etala (Technetium (99mTc) etarfolatide); Frattaquet ligand inhibitors, such as E-6011; Fyn tyrosine kinase inhibitors, such as Masitinib, Lafluolimus; G protein coupled receptor 15 antagonism Agents, such as GPR15 antagonists (rheumatoid arthritis/HIV-mediated bowel disease), Omeros; GABA A receptor modulators, such as laflulimus; glucocorticoid agonists, such as prednisolone, Verdaloc Glucocorticoid antagonists, such as REC-200; Glucocorticoid-induced leucine zipper stimulators, such as ART-G01; GM-CSF ligand inhibitors, such as nanometerab, MORAb-022, Lanzirumumab; GM-CSF receptor antagonists, such as morimumab; GM-CSF receptor modulators, such as GSK-3196165; growth regulatory protein alpha ligand inhibitors, such as T-5224; Hwith Kwith ATPase inhibitors, such as naproxen combined Combined with esomeprazole, naproxen combined with esomeprazole strontium, ketoprofen combined with omeprazole, KEO-25001, HC-1004, PN-40020; histamine H4 receptor antagonist, such as Toreforant, GD-48; histone deacetylase inhibitors, such as gemvenostat, CHR-5154; histone deacetylase-6 inhibitors, such as CKD-506; HIV- 1 gp120 protein inhibitors, such as Malawiro; HLA class II antigen DQ-2 α modulators, such as NexVax2; HLA class II antigen inhibitors, such as HLA-DR1/DR4 inhibitors (rheumatoid arthritis), Provid ; HLA class II antigen modulators, such as ARG-301, recombinant T cell receptor ligands (rheumatoid arthritis), Artielle; Hsp 70 family inhibitors, such as gusperimus trihydrochloride (gusperimus trihydrochloride) ; Hypoxia-inducible factor-1 inhibitors, such as 2-methoxyestradiol; IFNB gene stimulators, such as ART-102; I-κB kinase β inhibitors, such as IMD-2560, IMD-0560; I-κ B kinase inhibitors, such as bardoxolone methyl; IL-1 antagonists, such as rilonacept, IBPB-007-IL, antisense oligonucleotides (rheumatoid arthritis) (Leiden University Medical Center), recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis) (Shanghai Fudan, Zhangjiang Bio-Pharmaceutical); IL-10 agonist, such as peg-ilogen; IL-11 agonists, such as optelieus; IL-12 antagonists, such as ustekinumab, bevacizumab, ddRNAi therapeutics (rheumatoid arthritis) (Medistem/Benitec); IL-15 antagonists, such as AMG-714, BNZ-132-2; IL-17 antagonists, such as ixekizumab, sekukinumab, KD-025; IL-17 receptor modulators , Such as CNTO-6785; IL-2 agonists, such as interleukin-2 follow-up biologics; IL-2 antagonists, such as IB-RA (injectable, rheumatoid arthritis) (Innobioscience), IB-RA (Oral, rheumatoid arthritis) (Innobioscience), BNZ-132-2; IL-21 antagonists, such as NN-8828, BNZ-132-2; IL-23 antagonists, such as ustekinumab, shellfish Vallizumab; IL-3 antagonist, such as anti-IL-3 mAbs (rheumatoid arthritis) (University of Regen sburg); IL-4 agonists, such as SER-130-AMI; IL-6 antagonists, such as onokizumab, clezanizumab, shrukuumab, SA-237, tocilizumab Anti-, ALX-0061, FB-704A, OP-R003, peptide IL-6 antagonist, MEDI-5117, T-5224, humanized anti-IL-6 mAb, tocilizumab biosimilar, IL-6 neutralization Human antibody, anti-IL6 antibody, RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, Esonarimod, TA-383; IL-6 receptor modulator , Such as tocilizumab, tocilizumab biosimilars, RO-4877533; immunoglobulin antagonists, such as elaimod; immunoglobulin G1 agonists, such as canalizumab, infliximab biological Preferred drugs, infliximab biosimilar drugs, BX-2922, STI-002, HF-1020; immunoglobulin G1 antagonists, such as YHB-1411-2; immunoglobulin G1 modulators, such as CFZ-533, Rnzilumab; immunoglobulin G2 antagonists, such as denosumab; immunoglobulin G2 modulators, such as PF-547659; immunoglobulin gamma Fc receptor II modulators, such as MGD-010; immunoglobulin gamma Fc receptor IIB antagonists, such as XmAb-5871; immunoglobulin kappa modulators, such as lanziluzumab; immunoglobulin M antagonists, such as IB-RA (injectable, rheumatoid arthritis) (Innobioscience), IB-RA (oral, rheumatoid arthritis) (Innobioscience); inducible nitric oxide synthase inhibitors, such as SKLB-023; inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil; insulin Sensitizers, such as rosiglitazone, THR-0921, HE-3286, BLX-1002; integrin α-1/β-1 antagonists, such as SAN-300; integrin α-4/β-1 antagonists , Such as natalizumab; integrin antagonists, such as PEG-HM-3, CY-9652; interferon beta ligands, such as recombinant interferon beta-1a, TA-383; interferon gamma ligand, Subsequent biological preparations such as interferon gamma; interleukin 17A ligand inhibitors, such as ABT-122, bimeclizumab, ABBV-257; interleukin 17F ligand inhibitors, such as bimeclisumab; interleukin 23A inhibitors, such as guselkumab; interleukin ligands, such as IBPB-007-IL; interleukin receptor 17A antagonists, such as bridalumab; interleukin-1 Beta ligand inhibitors, such as canalizumab, linacrecept, T-5224, gevokizumab, BLX-100 2. LY-2189102, PMI-001, K-832, CDP-484; interleukin-10 ligand, such as PF-06687234; interleukin-2 ligand, such as ontac, recombinant interleukin -2. Follow-up biological preparations of interleukin-2, recombinant human interleukin-2, interleukin-2 (injectable); interleukin-4 ligand, such as Tetravil; interleukin -6 ligand inhibitors, such as Gillizumab, PF-4236921; Itk tyrosine kinase inhibitors, such as ARN-4079; JAK tyrosine kinase inhibitors, such as tofacitinib, SHR-0302, Se Dunib, Pefitinib, Tofacitinib deuterated analogues, SD-900, CVXL-0074; Jak1 tyrosine kinase inhibitors, such as ABT-494, Baritinib, Ruxolitinib (ruxolitinib) ), Fegotinib, Tofacitinib, Itacitinib, Pifitinib, NIP-585, CS-944X, YJC-50018, GLPG-0555, MRK-12; Jak2 tyrosine kinase Inhibitors, such as baritinib, luzotinib, CT-1578; JAK3 gene inhibitors, such as GBL-5b; Jak3 tyrosine kinase inhibitors, such as decernotinib, tofacitinib, Pifitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613; Jun amino terminal kinase inhibitors, such as IQ-1S; KCNA voltage-gated potassium channel-3 Modulators, such as MRAD-P1; Kelch-like ECH-related protein 1 modulators, such as dimethyl fumarate; Kit tyrosine kinase inhibitors, such as Imatinib, Masitinib; LanC-like protein 2 modulators , Such as BT-11; LITAF gene inhibitors, such as GBL-5b; lymphocyte function antigen-3 receptor antagonists, such as alefacept; Lyn tyrosine kinase inhibitors, such as Masitinib; Phage Mannose Receptor 1 modulator, such as Tc 99m Temanocept; MAdCAM inhibitor, such as PF-547659; MAP kinase modulator, such as SKLB-023; MAP3K2 gene inhibitor, such as GBL-5b; MAPKAPK5 inhibition Agents, such as GLPG-0259; matrix metalloproteinase inhibitors, such as GLPG-0259; MCL1 gene inhibitors, such as Celcib; MEK protein kinase inhibitors, such as binitinib, AD-GL0001; MEK-1 protein kinase Inhibitors, such as binitinib; MEK-2 protein kinase inhibitors, such as binitinib; membrane cupramine oxidase inhibitors, such as BTT-1023, PRX-167700, vepamilomab ; metalloproteinase-2 Inhibitors, such as ER G-240; metalloproteinase-9 inhibitors, such as GS-5745, ERG-240; midkine ligand inhibitors, such as CAB-102; mitochondrial 10 kDa heat shock protein stimulators, such as INV-103; mTOR Complex 1 inhibitors, such as everolimus; mTOR inhibitors, such as everolimus, tamsulolimus; NAD ADP ribosyltransferase stimulators, such as ontac; NAMPT gene inhibitors, such as ART-D01; NF κ B inhibitor stimulator, such as denosumab; NFAT gene inhibitor, such as T-5224; NFE2L2 gene stimulator, such as bardoxolone methyl; nicotinic acetylcholine receptor antagonist Agents, such as RPI-78, RPI-MN; NK cell receptor modulators, such as Masitinib; NKG2 AB activating NK receptor antagonists, such as monizumab; NKG2 D activating NK receptor antagonists, Such as NNC-0142-002; nuclear red blood cell 2-related factor 2 stimulators, such as dimethyl fumarate; nuclear factor kappa B inhibitors, such as bardoxolone methyl, IB-RA (injectable, Rheumatoid arthritis) (Innobioscience), dehydroxymethylepoxyquinomicin, HE-3286, IMD-0560, MP-42, Talunfobi, VGX-1027, SKLB-023, SP- 650003, MG-132, SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005; nuclear factor κB modulators, such as REM-1086; nuclear factor Kappa B p105 inhibitors, such as REM-1086; opioid growth factor receptor agonists, such as mitphaline acetate in combination with Trideca Teide acetate, FAR-404; opioid receptor delta antagonists, such as HS- 378; Osteoclast differentiation factor antagonists, such as Denosumab, cyclic peptide mimics (rheumatoid arthritis/osteoporosis) (University of Michigan); Osteoclast differentiation factor ligand inhibitors, such as Nozumab; oxidoreductase inhibitors, such as etodolac, imidazole salicylate; P2X7 purine receptor agonists, such as gemvenostat; p38 MAP kinase alpha inhibitors, such as VX-745, BMS-582949 Prodrugs, BMS-751324; p38 MAP kinase inhibitors, such as BCT-197, losmapimod, ARRY-797; PDE 4 inhibitors, such as Aprinast; PDE 5 inhibitors, such as PDE5 inhibitors (Rheumatoid Arthritis) (University of Rochester); PDGF receptor promotes Efficacy agents, such as oprin; PDGF receptor antagonists, such as imatinib, masitinib; PDGF-B ligand inhibitors, such as SL-1026; PERK gene inhibitors, such as binitinib ; Phosphoinositide-3 kinase δ inhibitors, such as Duvelisib, RP-6503, CT-732, INK-007, GNE-293; Phosphoinositide-3 kinase γ inhibitors, such as Duvelisib, RP-6503; Phospholipase A2 inhibitors, such as AVX-002, human-secreted phospholipase A2 type IIA-integrin binding inhibitory peptide (rheumatoid arthritis/asthma/Alzheimer's disease)/cancer ) (University of California), Davis, AK-106, methyl varespladib, Ro-31-4493, BM-162353, Ro-23-9358, YM-26734; platelet activating factor receptor Body antagonists, such as piperidone hydrochloride; PPAR gamma agonists, such as rosiglitazone, THR-0921, rosiglitazone XR, etalotz; programmed cell death protein 1 modulators, such as INSIX RA; Prostaglandin D synthase stimulators, such as HF-0220; protein arginine deiminase inhibitors, such as PAD inhibitors (rheumatoid arthritis) (Leiden University Medical Center/LURIS); protein tyrosine kinase Inhibitors, such as leflunomide; PurH purine biosynthetic protein inhibitors, such as mycophenolate mofetil; Rho-related protein kinase 2 inhibitors, such as KD-025; isolated enzyme inhibitors, such as anti-fibroblast activation Protein (FAP) antibody radiotracer (rheumatoid arthritis) (Hoffmann-La Roche/Radboud University); signal transduction protein CD24 modulators, such as CD24-IgFc; signal transduction inhibitors, such as imatinib; Sodium glucose transporter-2 inhibitors, such as THR-0921; sphingosine 1 phosphate phosphatase modulators, such as S1P modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoid arthritis) (Akaal Pharma); STAT3 gene inhibitors, such as bardoxolone methyl and victoria; superoxide dismutase stimulators, such as imisopasem manganese; SYK family tyrosine kinase inhibitors, such as MK -8457; Syk tyrosine kinase inhibitors, such as fostamatinib, entospletinib, KDDF-201110-06, HMPL-523, sedunib, AB-8779, GS-9876 , PRT-2607, CVXL-0074, CG-103065 and CG-0268 06; Multiligand proteoglycan-1 inhibitors, such as indarcinumab, lavtansine; T cell receptor antagonists, such as TCR inhibit SCHOOL peptide (systemic/topical, rheumatoid arthritis/dermatitis/scleroderma Disease) (SignaBlok), CII modifying peptide (rheumatoid arthritis) (Peking University); T cell receptor modulators, such as ARG-301; T cell surface glycoprotein CD28 inhibitors, such as Abasi Generic, Belacept, Abatacept biosimilars, RhuDex, BMS-188667; T cell surface glycoprotein CD28 stimulators, such as TAB-08; TAK1 binding protein modulators, such as epigallocatechin 3- Gallin esters; Talar modulators, such as short form Talar modulators (rheumatoid arthritis) (KayteeBio); T cell differentiation antigen CD6 inhibitors, such as Etolizumab; T cell surface glycoprotein CD8 inhibitors, such as tregasizumab; tenascin modulators, such as tregasin; TGF beta agonists, such as tregasizumab; thymononapeptide agonists, such as Syn-1002; TLR-2 antagonists Agents, such as VB-201, p-13; TLR-4 antagonists, such as VB-201, p-13; TLR-9 antagonists, such as p-13; TNFα ligand inhibitors, such as adalimumab Biosimilars, YHB-1411-2, Adalimumab, Infliximab, Infliximab biosimilars, Recombinant humanized anti-TNF-α monoclonal antibody, Pegylated Certuzumab, Ge Limumumab, orlizumab, AT-132, etanercept biosimilars, ISIS-104838, ISU-202, CT-P17, MB-612, Debio-0512, anti-TNF α human monoclonal antibody , Infliximab biologically better drug, UB-721, KN-002, DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420, GS- 071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-695501, CNTO-148, MYL-1401AABP-501, HOT-3010, BAX-2923, SCH- 215596, ABT-D2E7, BAT-1406, XPro-1595, Atsttrin, SSS-07, Golimumab biosimilar, TA-101, Adalimumab follow-up biologics, BLX-1002 ABX-0401, TAQ-588, Golimumab biosimilars, TeHL-1, Placulumab, PMI-001, tgAAV-TNFR: Fc, K-832, CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DOM-0200, DOM-0215, AME-527, anti-TNF-α mAb, GENZ-38167, BLX-1028, CYT- 020-TNFQb, CC-1080, CC-1069; TNFα ligand modulators, such as MM-A01-01, CDP-571, camobucol; TNF antagonists, such as etanercept, poly Glycated ertuzumab, etanercept follow-up biologics, etanercept biosimilars, DNX-114, TNF antagonist combined with IL-12 antagonist (rheumatoid arthritis) (University of Oxford) , BN-006, SCB-131, pegsunercept, GBL-5b, ACE-772, Onacep, DE-096, PN-0615, Lenercept, ITF-1779, MDL-201112, BAX-2200, SCB-808, DA-3853, HD-203; TNF gene inhibitors, such as GIBH-R-001-2; TNF receptor modulators, such as recombinant TNF receptor 2-Fc fusion protein Mutants, T-0001, tgAAV-TNFR: Fc; TNFSF11 gene inhibitors, such as denosumab; transcription factor p65 inhibitors, such as REM-1086; transcription factor RelB inhibitors, such as REM-1086; transferrin regulation Agents, such as methotrexate, MBP-Y003; tumor necrosis factor 13C receptor antagonists, such as VAY-736; tumor necrosis factor 15 ligand inhibitors, such as anti-TL1A antibody (rheumatoid arthritis/inflammatory bowel Tract diseases), NIAMS; tumor necrosis factor ligand 13 inhibitors, such as asecept; tumor necrosis factor ligand inhibitors, such as ABBV-257, etanercept biosimilars, ABT-122; type I IL-1 receptor antagonists, such as anakinra, anakinra biosimilars, anakinra follow-up biologics, AXXO; type I TNF receptor antagonists, such as NM-9405; type II TNF receptor modulators, such as etanercept, SCB-131, etanercept biosimilars, follow-up biologics of etanercept, BAX-2200, SCB-808, LBEC-0101, DMB-3853, DWP- 422, BT-D001, DA-3853; non-specific GPCR agonists, such as NCP-70X; VEGF receptor antagonists, such as 2-methoxyestradiol and NSC-650853, SL-1026; VEGF-2 receptor Antagonists, such as CG-026806; VEGF-2 receptor modulators , Such as VEGFR2 neutralizing antibody (rheumatoid arthritis) (University of Rochester); VEGF-B ligand inhibitors, such as CSL-346; apoptosis protein X sex-linked inhibitors, such as IAP inhibitors ( Oral) (Pharmascience); and Zap70 tyrosine kinase inhibitors, such as MK-8457, CT-5332.

Examples of combined metabolic disorders for metabolic diseases or conditions include (but are not limited to) diabetes (including type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, high serum cholesterol, and high blood cholesterol. Acid glycerides. Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and hypolipidemic agents. Other therapeutic agents used to treat metabolic disorders include insulin, sulfonylurea peroxisome proliferator-activated receptor gamma (PPAR- gamma) agonists, such as thiazolidinediones, such as pioglitazone (Pioglitazone), biguanides, α-glucose Glucosidase inhibitors, vitamin E and incretin mimics. Therefore, one aspect of the present invention is a method for treating metabolic diseases, which comprises administering the compound of the present invention in combination with one or more compounds suitable for treating metabolic diseases to individuals in need (especially human individuals).

Pharmaceutical composition Although the active ingredient may be administered alone, it is preferably presented as a pharmaceutical formulation (composition). The formulation of the present invention for both veterinary and human use includes at least one active ingredient as defined above, and its corresponding one or more acceptable carriers and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the physiology of the recipient.

The formulations include those suitable for the aforementioned administration routes. The formulation can conveniently be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical technology. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). These methods include the step of mixing the active ingredient with the inactive ingredients constituting one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely powdered solid carrier or both, and then shaping the product if necessary.

In certain embodiments, formulations suitable for oral administration are presented as discrete units, such as capsules, cachets, or lozenges each containing a predetermined amount of active ingredient.

In certain embodiments, the pharmaceutical formulation includes one or more compounds of the present invention, and one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical formulation containing the active ingredient can be in any form suitable for the intended method of administration. When used, for example, for oral use, tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. The compositions to be used for oral use can be prepared according to any method known in the technology of manufacturing pharmaceutical compositions, and these compositions can contain one or more agents, including sweeteners, flavoring agents, coloring agents and preservatives, In order to provide delicious preparations. Tablets containing the active ingredient mixed with pharmaceutically acceptable non-toxic excipients are acceptable, wherein the excipients are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents , Such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The lozenge can be uncoated or can be coated using known techniques (including microencapsulation) to delay disintegration and adsorption in the gastrointestinal tract, and thus provide a long-lasting effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

The amount of active ingredient that can be combined with inactive ingredients to make a dosage form will vary depending on the subject to be treated and the specific mode of administration. For example, in some embodiments, the dosage form for oral administration to humans contains about 1 mg to 1000 mg of active substance, which is combined with an appropriate and appropriate amount of carrier substance (for example, inactive ingredients or excipients). Excipient substances) are blended together. In certain embodiments, the carrier material ranges from about 5% to about 95% (weight:weight) of the total composition. In some embodiments, the pharmaceutical composition described herein contains about 1 mg to 800 mg, 1 mg to 600 mg, 1 mg to 400 mg, 1 mg to 200 mg, 1 mg to 100 mg, or 1 mg to 50 mg. mg compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain no more than about 400 mg of the compound of formula I. In some embodiments, the pharmaceutical composition described herein contains about 100 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

It should be understood that, in addition to the ingredients specifically mentioned above, the formulations disclosed herein may also include other agents known in the art regarding the type of formulation in question, for example, suitable for oral administration. The formulation may include flavoring agents.

There is further provided a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier.

The veterinary carrier is a substance suitable for the purpose of administering the composition and can be a solid, liquid or gaseous substance, which is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (lower dose), delivery method and pharmaceutical formulation, and will be determined by clinicians using conventional dose escalation studies.

Route of administration One or more compounds of formula I (referred to herein as active ingredients) or pharmaceutically acceptable salts thereof are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including intrabuccal and sublingual), transvaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and Its similar approach. It should be understood that the preferred route may vary with, for example, the condition of the recipient. The advantage of the compound of the present invention is that it is orally bioavailable and can be administered orally. Therefore, in one embodiment, the pharmaceutical composition described herein is an oral dosage form. In certain embodiments, the pharmaceutical composition described herein is an oral solid dosage form.

Formulation Example 1 Prepare hard gelatin capsules containing the following ingredients: Quantity ingredient (mg/capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules.

Formulation Example 2 A tablet formulation was prepared using the following ingredients: Quantity component (mg/tablet) Active ingredient 25.0 Microcrystalline cellulose 200.0 Colloidal silica 10.0 Stearic acid 5.0 Blending and extruding the components to form a tablet Agent.

Formulation Example 3 A dry powder inhaler formulation containing the following components was prepared: Ingredient wt% Active ingredient 5 Lactose 95 The active ingredient was mixed with lactose and the mixture was added to the dry powder inhaler.

Formulation Example 4 Prepared tablets each containing 30 mg of active ingredient as follows: Quantity ingredient (mg/tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% solution in sterile water (In the form of) 4.0 mg Sodium Carboxymethyl Starch 4.5 mg Magnesium Stearate 0.5 mg Talc 1.0 mg Total 120 mg

Pass the active ingredients, starch and cellulose through a No. 20 mesh U.S. sieve and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powder, which is then passed through a 16 mesh U.S. sieve. The resulting granules are dried at 50°C to 60°C and passed through a 16 mesh U.S. sieve. Subsequently, sodium carboxymethyl starch, magnesium stearate and talc, which had been passed through a No. 30 mesh US sieve in advance, were added to the granules, which were mixed and squeezed on a tablet press to obtain tablets each weighing 120 mg.

Formulation example 5 prepared suppositories each containing 25 mg of active ingredients as follows: Ingredients Quantity of active ingredients 25 mg saturated fatty acid glycerides 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in saturated fatty acid glycerides melted in advance using the minimum heat required. The mixture was then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 6 is prepared as follows to prepare a suspension containing 50 mg of active ingredient per 5.0 mL dose: Ingredient amount Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose ( 89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavoring and pigment appropriate amount of purified water 5.0 mL

The active ingredients, sucrose, and three gums are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Some of the sodium benzoate, flavor and color are diluted with water and added with stirring. Sufficient water is then added to produce the required volume.

Formulation Example 7 The subcutaneous formulation can be prepared as follows: Ingredient Quantity Active ingredient 5.0 mg Corn oil 1.0 mL

Formulation example 8 prepares an injectable preparation with the following components: active ingredient 2.0 mg/mL mannitol, USP 50 mg/mL gluconic acid, USP appropriate amount (pH 5 to 6) water (distilled, sterile) appropriate amount to 1.0 mL Nitrogen, appropriate amount of NF

Formulation Example 9 prepares a topical preparation with the following components: Ingredients g Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0 Mineral oil 5.0 Paraffin grease 0.10 Methyl p-hydroxybenzoate 0.15 Propyl p-hydroxybenzoate 0.05 BHA (butylated Hydroxyanisole) 0.01 Water appropriate amount to 100 Combine all the above ingredients except water and heat to 60°C with stirring. Then, under vigorous stirring, enough water at 60° C. was added to emulsify the ingredients, and then an appropriate amount of 100 g of water was added.

Formulation Example 10 Sustained release components Ingredient weight range% Active ingredient 50-95 Microcrystalline cellulose (filler) 1-35 Methacrylic acid copolymer 1-35 Sodium hydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5- 5.0 Magnesium stearate 0.5-5.0

The sustained release formulations of the present invention can be prepared as follows: the compound and the pH-related binder and any excipients that may be present are intimately mixed (dry blending). The dry blended mixture is then granulated in the presence of a strong alkali aqueous solution sprayed into the blended powder. The granules are dried, screened, mixed with a lubricant (such as talc or magnesium stearate) as appropriate, and extruded into a lozenge. The preferred strong alkaline aqueous solution is an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, in water (containing up to 25% of water-miscible solvents, such as lower alcohols, as appropriate) In the solution.

The obtained lozenges can be coated with a film-forming agent as appropriate for the purpose of distinguishing, covering the taste and improving the ease of swallowing. The film-forming agent will usually be present in an amount between 2% and 4% of the weight of the tablet. Suitable film formers are well known in the art and include hydroxypropyl methyl cellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/methyl butyl methacrylate copolymer , Eudragit ^® E-Röhm. Pharma) and similar. These film formers may contain colorants, plasticizers and other supplementary ingredients as appropriate.

The squeezed lozenge preferably has a hardness sufficient to withstand the squeezing force of 8 Kp. The size of the lozenge will largely depend on the amount of compound in the lozenge. The lozenge will contain 300 mg to 1100 mg of compound free base. Preferably, the lozenge will include an amount of free base of the compound in the range of 400 mg to 600 mg, 650 mg to 850 mg, and 900 mg to 1100 mg.

In order to influence the dissolution rate, the time for wet mixing the powder containing the compound is controlled. Preferably, the total powder mixing time, that is, the time the powder is exposed to the sodium hydroxide solution, will be in the range of 1 minute to 10 minutes, and preferably 2 minutes to 5 minutes. After the granules were made, the granules were removed from the self-made granulator and placed in a fluidized bed dryer for drying at about 60°C.

Formulation Example 11 The following ingredients were used to prepare a tablet formulation: Quantity ingredient (mg/tablet) Active ingredient 300.0 Microcrystalline cellulose 100.0 Colloidal silica 10.0 Stearic acid 5.0 The ingredients were blended and extruded to form a tablet Agent.

Examples The following examples are included to demonstrate specific embodiments of the present invention. Those familiar with the technology should understand that the technology disclosed in the following examples represents a technology that works well in practicing the present invention, and therefore can be regarded as a specific mode constituting its practice. However, according to the present invention, those skilled in the art should understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the present invention and still obtain the same or similar results.

List of abbreviations and acronyms abbreviation meaning °C Celsius Ac Acetyl aq. Water ATP Adenosine Triphosphate B ₂ Pin ₂ Bis(pinacol radical) diboron BOC Tertiary butoxycarbonyl Br Broad peak BSA Bovine serum albumin d Doublet DCM Dichloromethane dd ddd Double doublet Triplet DIPEA N,N-Diisopropylethylamine (Hünig's Base) DMA Dimethylacetamide DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSO Diabetes dt Double triplet DTT Dithiothreitol (Cleland's reagent) EC ₅₀ EDC Half maximum effective concentration 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide EDTA Ethylenediaminetetraacetic acid EGFR Epidermal growth factor receptor Eq equivalent ES/MS Electrospray mass spectrometry Et Ethyl EtOAc Ethyl acetate EtOH Ethanol (Ethanol/Ethyl alcohol) FBS Fetal Bovine Serum g Gram HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HCl hydrochloric acid HPLC High pressure liquid chromatography Hrs Hour HTRF® Homogeneous time-resolved fluorescence, registered trademark of Cisbio Bioassays (France, parc marcel boiteux 30200 codolet) Hz hertz IBD Inflammatory bowel disease IC ₅₀ Half maximum inhibitory concentration i-pr Isopropyl J Coupling constant (MHz) K ₃ PO ₄ Tripotassium Phosphate KOtBu KOAc LCMS Potassium tert-butoxide Potassium acetate Liquid chromatography mass spectrometry Li HMDS Lithium bis(trimethylsilyl)amide LiOH Lithium Hydroxide LiI Lithium Iodide LPS Lipopolysaccharide M Mol m Multiplet M+ Mass peak M+H+ Mass peak hydrogenation Me methyl MeCN Acetonitrile MeOH Methanol/Methyl alcohol MeLi Methyl lithium MeMgX Methyl magnesium halide (Grignard reagent), where X is fluoro, chloro, bromo or iodo Me ₆ Sn ₂ Hexamethyl distannane (hexamethyl distann) mg Milligrams MgSO ₄ Magnesium Sulfate MHz Megahertz Min minute ml/mL Milliliters mM Millimoles mmol Millimoles MS MsCl Mass spectrometry Methanesulfonyl chloride NBS N-Bromosuccinimide n- just nBu/Bu N-Butyl/normal Butyl n-BuLi N-butyl lithium NaH Sodium hydride NaHCO ₃ Sodium bicarbonate NaN ₃ Sodium Azide Na ₃ PO ₄ Trisodium Phosphate Na ₂ SO ₄ Sodium sulfate nL Nai Sheng nm NMP Nano 1-methylpyrrolidin-2-one NMR NMR NP-40 Nonylphenoxy polyethoxyethanol Pd-PEPPSI ^TM -IPent [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride Pen-Strep Penicillin-streptomycin (0.85% normal saline containing 5,000 units of penicillin G sodium salt and 5,000 μg streptomycin sulfate) Ph Phenyl q Quartet q.s. Sufficient to achieve the stated function RP Inverted RPMI Roswell Park Memorial Institute medium Rt Room temperature s Unimodal sat. Selectfluor® To SFC saturation Bis1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane (Trademark of Air Products and Chemicals) Supercritical fluid chromatography SiliaMetS® Thiol Silica-based palladium scavenger, registered trademark of Silicycle T THF TFA XPhos Pd G3 Triplet Tetrahydrofuran Trifluoroacetate Methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) Diphenyl)) Palladium(II)

實例A 1. Comparative Example A Comparative Example A is shown as Example 193 in the international patent application PCT/US2016/038861 published as WO 2016/210036 A1. The structure of Comparative Example A is:

Example A

2. Synthesis of intermediates and preparation of intermediates I-1 :

3,3 -diethoxy -2 -methanylpropionitrile potassium salt (I-1C) : 3,3-diethoxypropane-nitrile ( I-1A , 283.80 g, 1.98 Mo Ear) and methyl formate ( I-1B , 148.80 g, 2.48 mol) in anhydrous THF (1.1 L), add 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 mol) . During the 45 minutes of addition, the temperature was maintained in the range of 10°C to 15°C. After the addition, the resulting slurry was stirred at ambient temperature for 2 hours. Hexane (400 mL) was then added and stirring continued for another 20 minutes. The slurry was filtered, and the filter cake was washed with 1/1 of hexane/THF and dehydrated in a vacuum oven at 60° C. overnight to obtain I-1C . ¹ H-NMR (CD ₃ OD) is consistent with the desired structure.

Pyrrolo [1,2-b] despair 𠯤 3-carbonitrile (I- 1E): 3,3-diethoxy-2-making acyl propionitrile potassium salt (I-1C, 5.10 g, 24.36 The stirred suspension of mmol) was cooled to 0°C, and concentrated HCl (7.11 mL, 85.26 mmol) was added dropwise at a rate such that the internal temperature of the reaction did not exceed 20°C. After the addition was complete, the reaction was stirred at room temperature for 20 minutes. To this reaction mixture was added a solution of 1-aminopyrrole ( I-1D , 1.00 g, 12.18 mmol) in methanol (4.0 mL). After the addition, the reaction mixture was refluxed at 90°C for 2 hours. Upon completion of heating, the reaction was cooled to room temperature and concentrated to about half of the original volume. To the resulting residue was cautiously added saturated aqueous sodium bicarbonate solution until bubbling ceased. The solution was extracted with two portions of ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (eluent: EtOAc/hexane) to obtain I-1E . 1H NMR (400 MHz, chloroform- d ) δ 8.16-8.03 (m, 2H), 7.93 (ddd, J = 2.6, 1.4, 0.6 Hz, 1H), 7.04 (dd, J = 4.5, 2.7 Hz, 1H), 6.84 (dd, J = 4.6, 1.4 Hz, 1H).

7-bromo-pyrrolo [1,2-b] despair 𠯤 3-carbonitrile (I-1F): at the room temperature and the pyrrole [1,2-b] despair 𠯤 3-carbonitrile (I-1E , 840.0 mg, 5.9 mmol) in MeCN (30 mL), add N-bromosuccinimide in one portion. The reaction was stirred at room temperature for 30 minutes and then poured into a saturated aqueous sodium bicarbonate solution. The solution was concentrated in vacuo to remove acetonitrile. The resulting aqueous layer was extracted with three portions of EtOAc. The combined organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (eluent: EtOAc/hexane) to obtain I-1F . 1H NMR (400 MHz, chloroform- d ) δ 8.28 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.93 (d , J = 4.8 Hz, 1H).

7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [1,2-b] despair 𠯤 3-carbonitrile (I -1) : Fill the microwave vial with 7-bromopyrrolo[1,2-b]daz-3-carbonitrile ( I-1F , 416.5 mg, 1.9 mmol), bis(pinacol radical) diboron (762.1 mg, 3.0 mmol), potassium acetate (552.3 mg, 5.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (65.8 mg, 0.094 mmol). Dioxane (8.0 mL) and DMF (4.0 mL) were added, and the reaction mixture was degassed with argon bubbling for 2 minutes. The vial was sealed, and the reaction was heated at 120°C for 60 minutes in a microwave reactor. After cooling, the reaction mixture was filtered and concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with a second portion of EtOAc, and the combined organic layer was dried over sodium sulfate, filtered through a plug of celite, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent: EtOAc/hexane) to obtain I-1 . 1H NMR (400 MHz, chloroform- d ) δ 8.31 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 6.84 (d , J = 4.6 Hz, 1H), 1.41 (s, 12H).

6- 溴 -4- 氯菸鹼酸。 向6-溴-4-氯菸鹼酸甲酯(15 g，59.89 mmol)於甲醇(240 mL)中之溶液中添加含氫氧化鋰(2.93 g，119.77 mmol)之水(68 mL)。將溶液加熱至43℃持續隔夜，且隨後使其冷卻至室溫。添加鹽酸水溶液(1M，120 mL)且在真空中移除揮發物。所得漿液經過濾且用H₂ O洗滌，得到6-溴-4-氯菸鹼酸。 ES/MS：238.0 (M+H⁺ )。 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.03 (s, 1H)。 Preparation of intermediate product I-2 :

6- Bromo- 4 -chloronicotinic acid. To a solution of methyl 6-bromo-4-chloronicotinate (15 g, 59.89 mmol) in methanol (240 mL) was added water (68 mL) containing lithium hydroxide (2.93 g, 119.77 mmol). The solution was heated to 43°C overnight, and then allowed to cool to room temperature. Aqueous hydrochloric acid (1M, 120 mL) was added and the volatiles were removed in vacuo. The resulting slurry was filtered and washed with H ₂ O to obtain 6-bromo-4-chloronicotinic acid. ES/MS: 238.0 (M+H ⁺ ). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.03 (s, 1H).

(R)-6- Bromo- 4 -chloro -N-(2- fluoro- 3 -hydroxy- 3 -methylbutyl ) nicotinamide. To a solution of 6-bromo-4-chloronicotinic acid (3 g, 12.69 mmol) in DMF (42 mL) was added HATU (6.27 g, 16.49 mmol), (R)-4-amino-3-fluoro -2-methylbutan-2-ol hydrochloride (2.4 g, 15.23 mmol) and N,N-diisopropylethylamine (5.62 ml, 32.26 mmol). The resulting solution was stirred at room temperature overnight, and then diluted with ethyl acetate. The organic solution was washed with a saturated aqueous lithium chloride solution (3 times), then _{dried over Na 2} SO ₄ and then concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc/hexane) to obtain (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl) smoke Alkaline amide. ES/MS: 341.1 (M+H ⁺ ). 1H NMR (400 MHz, DMSO- d ₆ ) δ 8.88 (t, J = 5.5 Hz, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 4.82 (s, 1H), 4.28 (ddd, J = 49.3, 9.4, 2.0 Hz, 1H), 3.84-3.63 (m, 1H), 3.40-3.22 (m, 1H), 1.13 (d, J = 7.0 Hz, 6H).

(R) -4- chloro-6- (3-cyano-pyrrolo [1,2-b] despair 𠯤 7-yl) -N- (2- fluoro-3-hydroxy-3-methylbutyl) Nicotinamide (I-5) . To (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (0.2 g, 0.59 mmol) in DME (3.9 mL) Add 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]ta𠯤-3-methyl to the solution Nitrile (0.24 g, 0.9 mmol), XPhos Pd G3 (0.05 g, 0.06 mmol) and aqueous tripotassium phosphate (2M, 0.59 mL, 1.18 mmol). The resulting solution was degassed with argon and heated to 120°C in a microwave reactor for 12 minutes. The crude reaction mixture was purified by silica gel chromatography (eluent: EtOAc/hexane) to obtain (R)-4-chloro-6-(3-cyanopyrrolo[1,2-b]ta𠯤-7-yl )-N-(2-Fluoro-3-hydroxy-3-methylbutyl)nicotinamide. ES/MS: 402.2 (M+H ⁺ ).

The procedure of Example 3. The procedure of Example 1 and the compound: Example 1: (R) -6- (3- cyano-pyrrolo [1,2-b] despair 𠯤 7-yl) -N- (2- fluoro-3- hydroxy-3-methylbutyl) -4- (methylamino) niacinamide

6- Chloro- 4-( methylamino ) nicotinic acid methyl ester : To 4,6-dichloronicotinic acid methyl ester (0.5 g, 2.43 mmol) and methylamine hydrochloride (0.82 g, 12.16 mmol) in Add 1,8-diazabicyclo(5.4.0)undec-7-ene (1.8 ml, 12.04 mmol) to a solution in acetonitrile (10 mL) and water (0.3 mL). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated to dryness in vacuo and diluted with ethyl acetate. The resulting solution was washed with water and an aqueous sodium chloride solution. The resulting organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting material was _{purified by normal phase SiO 2} chromatography (eluent: ethyl acetate/hexane) to obtain the desired product. ES/MS: 201.180 (M+H ⁺ ).

6- Chloro- 4-( methylamino ) nicotinic acid : To 6-chloro-4-(methylamino)nicotinic acid methyl ester (0.38 g, 1.92 mmol) in MeOH (10 mL), THF (5 mL Add lithium hydroxide (0.12 g, 5.01 mmol) to a solution in water (5 mL). The solution was stirred at room temperature for 18 h, neutralized with HCl (1N, 5 mL), and concentrated to dryness in vacuo. The resulting crude material is used in the next step. ES/MS: 187.070 (M+H ⁺ ).

(R)-6- chloro -N-(2- fluoro- 3 -hydroxy- 3 -methylbutyl )-4-( methylamino ) nicotinamide : to 6-chloro-4-(methylamino) ) Nicotinic acid (0.36 g, 1.92 mmol) and (R)-4-amino-3-fluoro-2-methylbutan-2-ol (0.31 g, 2.56 mmol) in DMF (10 mL) Add HATU (0.97 g, 2.55 mmol) and N,N-diisopropylethylamine (1.5 ml, 8.61 mmol). The resulting solution was stirred at room temperature for 1 hour and diluted with ethyl acetate. The solution was washed with 5% aqueous lithium chloride solution (3x), dried over sodium sulfate, and concentrated in vacuo. The resulting material was _{purified by normal phase SiO 2} chromatography (eluent: ethyl acetate/hexane) to obtain the desired product. ES/MS: 290.472 (M+H ⁺ ).

(R) -6- (3- cyano-pyrrolo [1,2-b] despair 𠯤 7-yl) -N- (2- fluoro-3-hydroxy-3-methylbutyl) -4- ( Methylamino ) nicotinamide : To (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide (30 mg, 0.10 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]taka 𠯤- To the solution of 3-carbonitrile (39 mg, 0.15 mmol) and Xphos Pd G3 (9 mg, 0.011 mmol) in DME (1 mL) was added potassium phosphate aqueous solution (2M, 0.10 mL, 0.20 mmol). The resulting solution was degassed with argon for 2 min and heated at 120°C under microwave conditions for 20 min. The reaction mixture was filtered, and the resulting solid was washed with DMF. The filtrate was then concentrated in vacuo, and the crude material was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to obtain the product in the form of the trifluoroacetate salt. ES/MS: 397.283 (M+H ⁺ ). 1H NMR (400 MHz, methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.02 (d, J = 5.1 Hz , 1H), 7.76 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.42 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.93 (ddd, J = 36.4, 14.5, 2.2 Hz, 1H), 3.48 (ddd, J = 16.2, 14.5, 9.4 Hz, 1H), 3.19 (s, 3H), 1.28 (d, J = 1.7 Hz, 6H).

Step 2: Example 2: (R) -4 - ( ( cyanomethyl) amino) -6- (3-cyano-pyrrolo [1,2-b] despair 𠯤 7-yl) -N- ( 2- fluoro- 3 -hydroxy- 3 -methylbutyl ) nicotinamide

(R)-6- chloro- 4-(( cyanomethyl ) amino )-N-(2- fluoro- 3 -hydroxy- 3 -methylbutyl ) nicotinamide : to (R)-4 ,6-Dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (100 mg, 0.34 mmol) and aminoacetonitrile hydrochloride (47.03 mg, 0.51 mmol) Add N,N-diisopropylethylamine (0.2 mL, 1.12 mmol) to the slurry in DMA (1 mL). The resulting solution was then heated at 150°C under microwave conditions for 30 min. Additional aminoacetonitrile hydrochloride (47.03 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.12 mmol) were added and the reaction was heated under thermal conditions at 130°C for 16 hours. The solution was cooled to room temperature and diluted with ethyl acetate. The resulting slurry was filtered and the solid was washed with EtOAC. The resulting filtrate was combined and washed with ammonia chloride. The resulting organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting material was _{purified by normal phase SiO 2} chromatography (eluent: ethyl acetate/hexane) to obtain the desired product. ES/MS: 315.159 (M+H ⁺ ).

(R) -4 - ((cyanomethyl) amino) -6- (3-cyano-pyrrolo [1,2-b] despair 𠯤 7-yl) -N- (2- fluoro-3- Hydroxy- 3 -methylbutyl ) nicotinamide : To (R)-6-chloro-4-((cyanomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methyl Butyl)nicotinamide (53 mg, 0.17 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo [1,2-b]A 𠯤-3-carbonitrile (68 mg, 0.25 mmol) and Xphos Pd G3 (16 mg, 0.019 mmol) in DME (2 mL) were added potassium phosphate aqueous solution (2M, 0.17 mL, 0.34 mmol). The resulting solution was degassed with argon for 2 min and heated at 120°C under microwave conditions for 20 min. The reaction mixture was filtered, and the resulting solid was washed with DMF and MeOH. The filtrate was then concentrated in vacuo, and the crude material was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to obtain the product in the form of the trifluoroacetate salt. The material was further purified by normal phase SiO ₂ chromatography (eluent: methanol/dichloromethane) and lyophilized from acetonitrile and water (0.1% trifluoroacetic acid) to obtain the desired product. ES/MS: 422.250 (M+H ⁺ ). 1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.0 Hz, 2H), 8.10 (d, J = 5.1 Hz, 1H), 8.05 (s , 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.73 (s, 2H), 4.46 (ddd, J = 49.1, 9.4, 2.2 Hz, 1H), 3.98 (ddd, J = 36.6, 14.5, 2.2 Hz, 1H), 3.60-3.41 (m, 1H), 1.31 (d, J = 1.7 Hz, 6H).

Step 3: Example 3: 4 - (((R ) -1- cyanoethyl) amino) -6- (3-cyano-pyrrolo [1,2-b] despair 𠯤-7-yl) -N -((R)-2- fluoro- 3 -hydroxy- 3 -methylbutyl ) nicotinamide

4-(((R)-1 -amino- 1 -oxoprop- 2- yl ) amino )-6- chloro- N-((R)-2- fluoro- 3 -hydroxy- 3 -methyl Butyl ) nicotinamide : To (R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (200 mg, 0.68 mmol) And (R)-2-aminopropanamide hydrochloride (172 mg, 1.38 mmol) in DMA (3 mL) was added to the slurry of N,N-diisopropylethylamine (0.6 mL, 3.37 mmol) ). The resulting solution was then heated at 150°C under microwave conditions for 60 min. The obtained material was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to obtain the product in the form of trifluoroacetate. ES/MS: 347.521 (M+H ⁺ ). Table 1 : Compound Compound ES/MS m/z step name 1 397.3 1 (R)-6-(3-Cyanopyrrolo[1,2-b]ta𠯤-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-( Methylamino) Nicotinamide 2 422.3 2 (R)-4-((Cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]ta𠯤-7-yl)-N-(2-fluoro-3- Hydroxy-3-methylbutyl)nicotinamide 3 436.4 3 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pada-7-yl)-N-((R)- 2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide 4 436.3 3 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pada-7-yl)-N-((R)- 2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide 5 450.4 3 4-(((R)-1-cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]pada-7-yl)-N-((R)- 2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide 6 450.3 3 4-(((S)-1-Cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]ta𠯤-7-yl)-N-((R)- 2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide 7 436.5 2 (R)-4-((2-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pada-7-yl)-N-(2-fluoro- 3-hydroxy-3-methylbutyl)nicotinamide 8 450.7 2 (R)-4-((3-cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]pada-7-yl)-N-(2-fluoro- 3-hydroxy-3-methylbutyl)nicotinamide 9 450.5 3 (R)-4-((2-Cyanoprop-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]ta𠯤-7-yl)-N-(2- Fluoro-3-hydroxy-3-methylbutyl)nicotinamide 10 448.5 2 (R)-4-((1-cyanocyclopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]ta𠯤-7-yl)-N-(2-fluoro -3-Hydroxy-3-methylbutyl)nicotinamide Table 2 - NMR data of exemplary compounds Compound 1H-NMR 1 1H NMR (400 MHz, methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.02 (d, J = 5.1 Hz , 1H), 7.76 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.42 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.93 (ddd, J = 36.4, 14.5, 2.2 Hz, 1H), 3.48 (ddd, J = 16.2, 14.5, 9.4 Hz, 1H), 3.19 (s, 3H), 1.28 (d, J = 1.7 Hz, 6H) 2 1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.0 Hz, 2H), 8.10 (d, J = 5.1 Hz, 1H), 8.05 (s , 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.73 (s, 2H), 4.46 (ddd, J = 49.1, 9.4, 2.2 Hz, 1H), 3.98 (ddd, J = 36.6, 14.5, 2.2 Hz, 1H), 3.60-3.41 (m, 1H), 1.31 (d, J = 1.7 Hz, 6H). 3 1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 5.1 Hz , 1H), 8.07 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.15 (q, J = 6.9 Hz, 1H), 4.47 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H) , 3.97 (ddd, J = 36.4, 14.6, 2.2 Hz, 1H), 3.54 (ddd, J = 16.2, 14.5, 9.3 Hz, 1H), 1.85 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 1.7 Hz, 6H) 4 1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 5.0 Hz , 1H), 8.07 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.15 (q, J = 7.0 Hz, 1H), 4.46 (ddd, J = 49.0, 9.4, 2.2 Hz, 1H) , 3.99 (ddd, J = 36.3, 14.5, 2.1 Hz, 1H), 3.60-3.43 (m, 1H), 1.85 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 1.7 Hz, 6H). 5 1H NMR (400 MHz, methanol-d4) δ 8.77 (t, J = 1.8 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.08 (dd , J = 5.2, 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.23 (dd, J = 5.1, 1.4 Hz, 1H), 5.05 (t, J = 6.9 Hz, 1H), 4.45 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.94 (ddd, J = 36.5, 14.6, 2.3 Hz, 1H), 3.52 (td, J = 15.2, 9.3 Hz, 1H), 2.17 (p, J = 7.2 Hz, 2H), 1.29 (d, J = 1.6 Hz, 6H), 1.25 (td, J = 7.4, 1.4 Hz, 3H). 6 1H NMR (400 MHz, methanol-d4) δ 8.71 (d, J = 2.7 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.24 (s , 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 5.0 Hz, 1H), 4.80 (d, J = 6.3 Hz, 1H), 4.43 (ddd, J = 49.0, 9.2, 2.4 Hz, 1H), 4.09-3.80 (m, 1H), 3.49 (ddd, J = 15.8, 14.3, 9.7 Hz, 1H), 2.14 (p, J = 7.2 Hz, 2H), 1.29 (d, J = 1.8 Hz, 6H), 1.27-1.18 (m, 3H). 7 1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.63 (s, 1H), 8.09 (d, J = 5.0 Hz , 1H), 7.96 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J = 49.1, 9.4, 2.2 Hz, 1H), 4.10-3.85 (m, 3H), 3.52 ( ddd, J = 16.2, 14.5, 9.4 Hz, 1H), 2.97 (t, J = 6.5 Hz, 2H), 1.31 (d, J = 1.7 Hz, 6H). 8 1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.05 (d, J = 5.1 Hz , 1H), 7.93 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.45 (ddd, J = 49.0, 9.3, 2.2 Hz, 1H), 3.97 (ddd, J = 36.3, 14.6, 2.2 Hz, 1H), 3.74 (t, J = 7.1 Hz, 2H), 3.51 (ddd, J = 16.2, 14.6, 9.3 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.13 (p, J = 7.0 Hz, 2H), 1.31 (d, J = 1.7 Hz, 6H). 9 1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.77 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.57 (s, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 3.96 (ddd, J = 36.5, 14.6, 2.1 Hz, 1H), 3.53 (ddd, J = 16.1, 14.6, 9.4 Hz, 1H), 1.98 (s, 6H), 1.31 (d, J = 1.7 Hz, 6H). 10 1H NMR (400 MHz, methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.43 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.94 (ddd, J = 36.3, 14.6, 2.1 Hz, 1H), 3.49 (ddd, J = 16.2, 14.6, 9.3 Hz, 1H), 1.97-1.84 (m, 2H), 1.64-1.53 (m, 2H), 1.29 (d, J = 1.6 Hz, 6H) .

Bioassays Perform bioassays to measure the activity against TNFα and IRAK4. As summarized in Table 3, the test compound is an inhibitor of IRAK4.

The test procedure based on IRAK4 monocyte TNFA cells: Thaw the cryopreserved human monocyte (stem cell technology), and use GlutaMAX TM (Gibco® 200 mM L-propylamine-L-glutamine ^{containing 10% FBS).} Acid) (10 mM HEPES, 1× penicillin-streptomycin, 55 µM ß-mercaptoethanol, 1 mM sodium pyruvate) in RPMI medium diluted to 0.125×10 ⁶ cells/ml, and restored at 37°C 2 Hour. The cell suspension was then seeded on a black 384-well Greiner transparent bottom culture plate at a density of 5,000 cells/well. The culture plate was pre-spotted with test compounds and serially diluted in DMSO, where an Echo 550 acoustic liquid dispenser (Labcyte®) was used to deliver 40 nanoliters/well to obtain a final DMSO concentration of 0.1%. The coated cells were treated with the compound at 37°C for 1 hour. The cells were then stimulated with 50 pg/ml LPS (Sigma), excluding the column outside the culture plate for the unstimulated cell control wells. The cells were incubated for another 4 hours at 37°C. The cells were then spun out of the culture medium, and a 5 μl sample was taken and the TR-FRET human TNFα detection system (CisBio) was used to analyze the total TNFα content. This system uses two labeled antibodies (cryptate and XL665) that bind to two different epitopes of the TNFα molecule and generate a FRET signal proportional to the concentration of TNFα in the sample. Mix the detection antibodies at 50:50, and dispense 5 µL into each well. Cover the culture plate with a transparent seal and incubate overnight at room temperature. In the next morning, the Envision 2103 multi-label reader (PerkinElmer) was used to read the culture plate with excitation/emission/FRET emission at 340 nm/615 nm/665 nm, respectively. The fluorescence intensity at the emission wavelengths of 615 nm and 665 nm is expressed as a ratio (665 nm/615 nm). Calculate the control percentage as follows: control% = 100 × (ratio _sample -ratio _{0% stimulation} )/(ratio _{100% stimulation} -ratio _{0% stimulation} ) where unstimulated cells (0% stimulation) are negative controls and stimulated Cells (100% stimulation) were used as a positive control.

IRAK4 biochemical analysis step: Measure the activity of IRAK4 enzyme (Carna Biosciences, Chuo-ku, Kobe, Japan) by detecting the phosphorylated peptide substrate using an antibody against the phosphorylated peptide substrate. This is a time-lapse fluorescence resonance energy transfer (TR-FRET) immunoassay based on STK1 KinEASE analysis (Cisbio, Bedford, Massachusetts). The analysis was designed to be a simple two-step end-point analysis (5 µl enzyme reaction followed by 5 µl stop and detection solution) in a ProxiPlate-384 Plus plate (Perkin Elmer, Waltham, Massachusetts). The non-selective kinase inhibitor Staurosporine was used as a positive control. Use Labcyte® Echo 550 Liquid Disposal System to spot the compound diluted in DMSO into a 384-well culture dish, and then add IRAK4 enzyme and peptide matrix. The reaction solution was delivered using Multi-Flo (Bio-Tek Instruments). The enzyme and peptide solution was incubated with the compound for 15 minutes at room temperature, and then the reaction was initiated by adding ATP. The standard 5 μl reaction mixture contains 500 μM ATP, 2 μM peptide (STK1 peptide), 0.75 nM in reaction buffer (50 mM HEPES, pH 7.0, 0.02% NaN ₃ , 0.01% BSA, 0.1 mM orthovanadate, 5 mM MgCl ₂ , 0.025% NP-40, 1 mM DTT) in IRAK4. After incubating for 120 minutes at room temperature, add 5 μl stop and detection solution (1:100 cryptate-labeled anti-phosphopeptide antibody solution and 50 mM HEPES pH 7.0 detection buffer containing sufficient EDTA Of 125 nM tracer). The plate was then incubated for another 60 minutes at room temperature and read using an Envision 2103 multi-label reader (PerkinElmer) with excitation/emission/FRET emission at 340 nm/615 nm/665 nm, respectively. The fluorescence intensity at the emission wavelengths of 615 nm and 665 nm is expressed as a ratio (665 nm/615 nm). The inhibition percentage is calculated as follows: Inhibition% = 100 × (Ratio _sample -Ratio _{0% inhibition} )/(Ratio _{100% inhibition} -Ratio _{0% inhibition} ) 0% inhibition value comes from control wells without inhibitor. The 100% inhibition value comes from a control well containing a saturated amount of the known inhibitor staurosporine.

Liver stability: Metabolic stability of hepatocytes stored at low temperature : Complete HT medium is prepared by adding 1 mL of Torpedo antibiotic mixture to 45 mL of InVitroGRO ^TM HT medium. Supplementary D KHB medium is composed of amikacin (84 mg/mL), calcium chloride (1 mM), gentamicin (84 µg/mL), HEPES (20 mM), heptanoic acid (4.2 µM) and KrebsHenseleit buffer composed of sodium bicarbonate (28.5 mM), and the pH was adjusted to 7.4 at 37°C using 1 M NaOH or 1 M HCl. Human hepatocytes stored at low temperature were collected from ten adult donors (Celsis, batch: HBZ). The vial containing cryopreserved liver cells was removed from liquid nitrogen and then immersed in a 37°C water bath. The vials were gently shaken until the contents were thawed, and then emptied to 48 mL of pre-warmed complete HT medium in a 50 mL conical tube. Resuspend the remaining cells in the vial and 1.0 mL of pre-warmed complete HT medium and add to the conical tube. The test tube was capped and then gently inverted several times to resuspend the liver cells. The cell suspension was centrifuged at 50×g for 5 minutes at room temperature and the supernatant was discarded. Slightly vortex the centrifuge tube to loosen the cell aggregates and add supplemental KHB medium to obtain a target density of ^{2×10 6 cells/ml.} The total number of cells and the ratio of living cells were measured by the trypan blue dye discharge method using a hemocytometer.

For incubation, add an aliquot of the hepatocyte suspension (250 μL containing 500,000 cells) to the duplicate wells in a 24-well plate to supplement 250 μL of 2 μM test compound in KHB or metabolic stability control In. The final concentration of the incubation is 1×10 ⁶ cells/ml and 1 μM test compound. 7-Hydroxycoumarin and testosterone, compounds known to be effectively metabolized by hepatocytes were used as positive controls in parallel incubation (the final concentration of each compound was 2 μM). Cultivation was performed at 37°C in a humid atmosphere of 95% air/5% CO ₂ (v/v) with gentle shaking. An aliquot (50 μL) was removed after 0, 1, 3, and 6 hours and added to 100 μL IS/Q quench solution. After the completion, add 150 μL of water, centrifuge each dish at 3000×g for 10 min, and use a Micromass Quattro Premier mass spectrometer coupled with an Agilent 1200 Series HPLC system with a Leap Technologies HTC PAL autosampler as described below An aliquot of the supernatant was analyzed on the instrument.

Liquid chromatography - mass spectrometry : quantification of test compounds and metabolic stability controls was performed on a Micromass Quattro Premier XL tandem triple quadrupole mass spectrometer coupled with an Agilent 1200 Series HPLC system with Leap Technologies HTC PAL autosampler Measure the analyte/internal standard peak area ratio (PAR) to perform. The column used is Phenomenex ^® MercuryMS ^TM , Synergi Max-RP (100 Å pore size, 2.5 μm particle size, 20 × 2.0 mm). Mobile phase A consists of 0.2% (v/v) formic acid in 99% water/1% acetonitrile (v/v). Mobile phase B consists of 0.2% (v/v) formic acid in 5% water/95% acetonitrile (v/v). Dissolution is achieved by the following series of linear gradients: initial condition 0% B, hold for 30 s, then increase to 100% B after 90 s, and then return to the initial condition after 1 s. Rebalance the system between injections for a minimum of 60 s. The sample injection volume is 10 μL.

LTP plasma protein binding : Prepare a stock solution containing the test compound dimethylsulfoxide (DMSO) at a final concentration of 10 mM and use it in all experiments.

Commercially available chemicals were obtained from Sigma-Aldrich (St. Louis, MO) and VWR (West Chester, PA). The cell culture medium (CCM) is Gibco Dulbecco's modified Eagle's medium (DMEM) with 10% (v/v) fetal bovine serum.

Balanced dialysis test : pooled plasma (from at least 3 males and 3 females) comes from humans, beagle dogs, Sprague-Dawley rats, cynomolgus monkeys (cynomolgus) monkey) and rhesus monkey. Sodium ethylenediaminetetraacetate is used as an anticoagulant.

Competitively balanced dialysis was performed at 37°C using human plasma relative to CCM containing 10% fetal bovine serum, and a sample with a final concentration of 2 μM on both sides of the matrix. Before the study, the dialysis membrane was immersed in 0.133 M phosphate buffer pH 7.4 for approximately one hour. Place the spiked plasma (1 mL) and CCM (1 mL) on the opposite side of the combined dialysed cells. To assess the recovery, after a 24-hour equilibration period in a 37°C water bath, the plasma sample was discharged into a pre-weighed polypropylene test tube containing 1 mL of CCM (no compound) and the CCM sample was discharged to a relevant blank containing 1 mL Pre-weighed test tube of plasma. Measure and record the weight of plasma and CCM after dialysis for calculation.

Liquid chromatography - Mass spectrometry : The test compound quantification was performed by measuring the analyte/internal standard peak area ratio (PAR) on a Q-Exactive mass spectrometer coupled with an Agilent 1260 Series HPLC system with a Leap Technologies HTS PAL autosampler. Mobile phase A consists of 0.2% (v/v) formic acid in 99% water/1% acetonitrile (v/v). Mobile phase B consists of 0.2% (v/v) formic acid in 5% water/95% acetonitrile (v/v). The sample injection volume is 10 μL.

Determination of pK _a: Sample preparation: Preparation of the final concentration of dimethyl sulfoxide containing the test compound of 10 mM (DMSO) in the stock solution and used in all experiments. The DMSO stock solution was thawed, spinned, and sonicated in a 40°C water bath to facilitate dissolution.

pK _a analysis: 10mM DMSO stock solution was diluted with 10mM HCl 100-fold to a final compound concentration of up to 100 μm and 1% DMSO. The compounds were then transferred to 24 consecutive wells of a 96-well PCR plate for analysis using an aqueous method. For compounds that do not provide high-quality information by aqueous methods, dilute the 10mM DMSO stock solution 100 times with 2mM HCl and methanol so that the final concentration of methanol is 60%, the compound concentration is 100 μm, and the DMSO concentration is 1%. The compounds were transferred to 24 consecutive wells of a 96-well culture plate for analysis using the co-solvent method. Analysis: Use pKa PRO analyzer (AATI, Ames, IA) to obtain all data. For the aqueous method, electrophoretic separation is performed in parallel at 24 different pH values, thereby providing a direct measurement of the charge of all compounds relative to pH. The compound was detected by UV at 228 nm. The average pH interval between buffer points is 0.4 pH units, covering the typical pH range of 1.7 to 11.2.

The co-solvent method is suitable for the analysis of compounds with low water solubility (usually predicted internal solubility of 10 μg/ml). The average pH interval between buffer points is 0.4 pH units, covering the pH range of 1.7 to 11.2. Four consecutive CE rounds were performed for each compound starting with 60% co-solvent buffer and reduced to 30% co-solvent buffer.

Norfloxacin (Norfloxacin) is used as a daily efficacy indicator standard.

Calculation of the result: predict the total value of pKa value by using pKa Estimator® software (AATI, Ames, IA) to correlate mobility and compound molecular weight.

The automated hERG assay performed in Charles River-Cleveland ( previously ChanTest) uses FASTPatch® assay (Charles River) to test in vitro the effects of various compounds on the colonized hERG potassium channel encoded by the KCNH2 gene and stably expressed in HEK293T cells . The vehicle, test and control formulations were prepared by diluting DMSO stock solution in HB-PS (HEPES buffered physiological saline solution) and delivered to the cells via the QPatch robotic pipetting system to reach a final concentration of 0.3% DMSO. Test compounds with final concentrations of 0.3, 1, 3, 10, and 30 μM were applied to cells separated by solution exchange in increasing order of at least three minutes intervals (n ≥ 3, where n = number of cells/concentration). The positive control (50 nM Cisparide) was applied in the same way. Use up to 48 patch clamp amplifiers in parallel in the QPatchHT® or QPatchHTX® system to record cell membrane currents at room temperature, and use only verified whole-cell recordings (seal resistance ≥ 200 MΩ and leakage current ≤ 25 % Channel current) of the cell. Use a stimulus voltage mode consisting of a 500 ms pre-pulse to -40 mV, a 2-second start pulse to +40 mV, and a 2-second test pulse to -40 mV to measure the onset and blocking of hERG current. This pulse pattern repeats continuously from the holding potential -80 mV at 10-second intervals. For each concentration tested, a Nephelostar reader was used to measure the light dispersion from a 635 nm laser source to perform TurboSol analysis of the solubility of the test compound. Based on the verification experiment, the light dispersion four times higher than the background level is considered as an indication of the presence of particles in the suspension. The results of the in vitro assay are shown in Table 3 below: Table 3 Compound IC ₅₀ HTRF (nM) EC ₅₀ TNF (nM) Protein Adj.EC ₅₀ TNF (nM) Human liver stability (L/h/kg) pK _a hERG IC ₅₀ (uM) A <1 twenty three 504 0.20 6.1 3.9 1 2 50 383 0.05 6.6 1.7 2 <1 19 232 0.13 5.1 ＞10 3 <1 14 191 0.08 4.9 ＞30 4 2 115 5 1 60 6 5 267 7 164 8 <1 33 0.14 5.9 3.5 9 <1 49 0.26 4.8 10 <1 35 0.22

Claims (6)

A compound of formula (II):

Or a pharmaceutically acceptable salt or structural isomer thereof, wherein: R ¹ is H, D or methyl, R ² is H, D or methyl, or R ¹ and R ² together with their attached carbon Together the atoms form a cyclopropyl group. The compound of claim 1, wherein R ¹ is H. The compound of claim 1, wherein R ¹ is a methyl group. A compound of formula (III):

, Or a pharmaceutically acceptable salt or deuterated analog thereof, wherein: R ¹ is H, D or methyl; and R ² is H, D or methyl. A compound

; Or its pharmaceutically acceptable salt. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.